Before his succession, George was granted the royal arms differenced by a label of five points Azure, the centre point bearing a fleur-de-lis Or on 27 July 1749. Upon his father's death, and along with the dukedom of Edinburgh and the position of heir-apparent, he inherited his difference of a plain label of three points Argent. In an additional difference, the crown of Charlemagne was not usually depicted on the arms of the heir, only on the Sovereign's.

George's grandfather, King George II, disliked the Prince of Wales, and took little interest in his grandchildren. However, in 1751 the Prince of Wales died unexpectedly from a lung injury, and George became heir apparent to the throne. He inherited his father's title of Duke of Edinburgh. Now more interested in his grandson, three weeks later the King created George Prince of Wales (the title is not automatically acquired).

In the spring of 1756, as George approached his eighteenth birthday, the King offered him a grand establishment at St James's Palace, but George refused the offer, guided by his mother and her confidant, Lord Bute, who would later serve as Prime Minister. George's mother, now the Dowager Princess of Wales, preferred to keep George at home where she could imbue him with her strict moral values.

In 1759, George was smitten with Lady Sarah Lennox, sister of the Duke of Richmond, but Lord Bute advised against the match and George abandoned his thoughts of marriage. "I am born for the happiness or misery of a great nation," he wrote, "and consequently must often act contrary to my passions." Nevertheless, attempts by the King to marry George to Princess Sophie Caroline of Brunswick-Wolfenbüttel were resisted by him and his mother; Sophie married the Margrave of Bayreuth instead.

The following year, at the age of 22, George succeeded to the throne when his grandfather, George II, died suddenly on 25 October 1760, two weeks before his 77th birthday. The search for a suitable wife intensified. On 8 September 1761 in the Chapel Royal, St James's Palace, the King married Princess Charlotte of Mecklenburg-Strelitz, whom he met on their wedding day. A fortnight later on 22 September both were crowned at Westminster Abbey. George remarkably never took a mistress (in contrast with his grandfather and his sons), and the couple enjoyed a genuinely happy marriage until his mental illness struck. They had 15 children—nine sons and six daughters. In 1762, George purchased Buckingham House (on the site now occupied by Buckingham Palace) for use as a family retreat. His other residences were Kew and Windsor Castle. St James's Palace was retained for official use. He did not travel extensively, and spent his entire life in southern England. In the 1790s, the King and his family took holidays at Weymouth, Dorset, which he thus popularised as one of the first seaside resorts in England.

In May 1762, the incumbent Whig government of the Duke of Newcastle was replaced with one led by the Scottish Tory Lord Bute. Bute's opponents worked against him by spreading the calumny that he was having an affair with the King's mother, and by exploiting anti-Scottish prejudices amongst the English. John Wilkes, a member of parliament, published The North Briton, which was both inflammatory and defamatory in its condemnation of Bute and the government. Wilkes was eventually arrested for seditious libel but he fled to France to escape punishment; he was expelled from the House of Commons, and found guilty in absentia of blasphemy and libel. In 1763, after concluding the Peace of Paris which ended the war, Lord Bute resigned, allowing the Whigs under George Grenville to return to power.

Later that year, the Royal Proclamation of 1763 placed a limit upon the westward expansion of the American colonies. The Proclamation aimed to divert colonial expansion to the north (to Nova Scotia) and to the south (Florida). The Proclamation Line did not bother the majority of settled farmers, but it was unpopular with a vocal minority and ultimately contributed to conflict between the colonists and the British government. With the American colonists generally unburdened by British taxes, the government thought it appropriate for them to pay towards the defence of the colonies against native uprisings and the possibility of French incursions. The central issue for the colonists was not the amount of taxes but whether Parliament could levy a tax without American approval, for there were no American seats in Parliament. The Americans protested that like all Englishmen they had rights to "no taxation without representation". In 1765, Grenville introduced the Stamp Act, which levied a stamp duty on every document in the British colonies in North America. Since newspapers were printed on stamped paper, those most affected by the introduction of the duty were the most effective at producing propaganda opposing the tax. Meanwhile, the King had become exasperated at Grenville's attempts to reduce the King's prerogatives, and tried, unsuccessfully, to persuade william Pitt the Elder to accept the office of Prime Minister. After a brief illness, which may have presaged his illnesses to come, George settled on Lord Rockingham to form a ministry, and dismissed Grenville.

Lord Rockingham, with the support of Pitt and the King, repealed Grenville's unpopular Stamp Act, but his government was weak and he was replaced in 1766 by Pitt, whom George created Earl of Chatham. The actions of Lord Chatham and George III in repealing the Act were so popular in America that statues of them both were erected in New York City. Lord Chatham fell ill in 1767, and the Duke of Grafton took over the government, although he did not formally become Prime Minister until 1768. That year, John Wilkes returned to England, stood as a candidate in the general election, and came top of the poll in the Middlesex constituency. Wilkes was again expelled from Parliament. Wilkes was re-elected and expelled twice more, before the House of Commons resolved that his candidature was invalid and declared the runner-up as the Victor. Grafton's government disintegrated in 1770, allowing the Tories led by Lord North to return to power.

George III hoped that "the tongue of malice may not paint my intentions in those colours she admires, nor the sycophant extoll me beyond what I deserve", but in the popular mind George III has been both demonised and praised. While very popular at the start of his reign, by the mid-1770s George had lost the loyalty of revolutionary American colonists, though it has been estimated that as many as half of the colonists remained loyal. The grievances in the United States Declaration of Independence were presented as "repeated injuries and usurpations" that he had committed to establish an "absolute Tyranny" over the colonies. The Declaration's wording has contributed to the American public's perception of George as a tyrant. Contemporary accounts of George III's life fall into two camps: one demonstrating "attitudes dominant in the latter part of the reign, when the King had become a revered symbol of national resistance to French ideas and French power", while the other "derived their views of the King from the bitter partisan strife of the first two decades of the reign, and they expressed in their works the views of the opposition".

Lord North's government was chiefly concerned with discontent in America. To assuage American opinion most of the custom duties were withdrawn, except for the tea duty, which in George's words was "one tax to keep up the right [to levy taxes]". In 1773, the tea ships moored in Boston Harbor were boarded by colonists and the tea thrown overboard, an event that became known as the Boston Tea Party. In Britain, opinion hardened against the colonists, with Chatham now agreeing with North that the destruction of the tea was "certainly criminal". With the clear support of Parliament, Lord North introduced measures, which were called the Intolerable Acts by the colonists: the Port of Boston was shut down and the charter of Massachusetts was altered so that the upper house of the legislature was appointed by the Crown instead of elected by the lower house. Up to this point, in the words of Professor Peter Thomas, George's "hopes were centred on a political solution, and he always bowed to his cabinet's opinions even when sceptical of their success. The detailed evidence of the years from 1763 to 1775 tends to exonerate George III from any real responsibility for the American Revolution." Though the Americans characterised George as a tyrant, in these years he acted as a constitutional monarch supporting the initiatives of his ministers.

The American War of Independence was the culmination of the civil and political American Revolution resulting from the American Enlightenment. Brought to a head over the lack of American representation in Parliament, which was seen as a denial of their rights as Englishmen and often popularly focused on direct taxes levied by Parliament on the colonies without their consent, the colonists resisted the imposition of direct rule after the Boston Tea Party. Creating self-governing provinces, they circumvented the British ruling apparatus in each colony by 1774. Armed conflict between British regulars and colonial militiamen broke out at the Battles of Lexington and Concord in April 1775. After petitions to the Crown for intervention with Parliament were ignored, the rebel Leaders were declared traitors by the Crown and a year of fighting ensued. The colonies declared their independence in July 1776, listing grievances against the British king and legislature while asking the support of the populace. Among George's other offences, the Declaration charged, "He has abdicated Government here ... He has plundered our seas, ravaged our Coasts, burnt our towns, and destroyed the lives of our people." The gilded Equestrian statue of George III in New York was pulled down. The British captured the city in 1776, but lost Boston, and the grand strategic plan of invading from Canada and cutting off New England failed with the surrender of the British Lieutenant-General John Burgoyne at the Battle of Saratoga.

George III is often accused of obstinately trying to keep Great Britain at war with the Revolutionaries in America, despite the opinions of his own ministers. In the words of the Victorian author George Trevelyan, the King was determined "never to acknowledge the independence of the Americans, and to punish their contumacy by the indefinite prolongation of a war which promised to be eternal." The King wanted to "keep the rebels harassed, anxious, and poor, until the day when, by a natural and inevitable process, discontent and disappointment were converted into penitence and remorse". However, more recent historians defend George by saying in the context of the times no king would willingly surrender such a large territory, and his conduct was far less ruthless than contemporary monarchs in Europe. After Saratoga, both Parliament and the British people were in favour of the war; recruitment ran at high levels and although political opponents were vocal, they remained a small minority. With the setbacks in America, Prime Minister Lord North asked to transfer power to Lord Chatham, whom he thought more capable, but George refused to do so; he suggested instead that Chatham serve as a subordinate minister in Lord North's administration, but Chatham refused to co-operate. He died later in the same year. In early 1778, France (Britain's chief rival) signed a treaty of alliance with the United States and the conflict escalated. The United States and France were soon joined by Spain and the Dutch Republic, while Britain had no major allies of its own. Lord Gower and Lord Weymouth both resigned from the government. Lord North again requested that he also be allowed to resign, but he stayed in office at George III's insistence. Opposition to the costly war was increasing, and in June 1780 contributed to disturbances in London known as the Gordon riots.

As late as the Siege of Charleston in 1780, Loyalists could still believe in their eventual victory, as British troops inflicted heavy defeats on the Continental forces at the Battle of Camden and the Battle of Guilford Court House. In late 1781, the news of Lord Cornwallis's surrender at the Siege of Yorktown reached London; Lord North's parliamentary support ebbed away and he resigned the following year. The King drafted an abdication notice, which was never delivered, finally accepted the defeat in North America, and authorised peace negotiations. The Treaties of Paris, by which Britain recognised the independence of the American states and returned Florida to Spain, were signed in 1782 and 1783. When John Adams was appointed American Minister to London in 1785, George had become resigned to the new relationship between his country and the former colonies. He told Adams, "I was the last to consent to the separation; but the separation having been made and having become inevitable, I have always said, as I say now, that I would be the first to meet the friendship of the United States as an independent power."

For George III, Pitt's appointment was a great victory. It proved that he was able to appoint Prime Ministers on the basis of his own interpretation of the public mood without having to follow the choice of the current majority in the House of Commons. Throughout Pitt's ministry, George supported many of Pitt's political aims and created new peers at an unprecedented rate to increase the number of Pitt's supporters in the House of Lords. During and after Pitt's ministry, George III was extremely popular in Britain. The British people admired him for his piety, and for remaining faithful to his wife. He was fond of his children, and was devastated at the death of two of his sons in infancy in 1782 and 1783 respectively. Nevertheless, he set his children a strict regimen. They were expected to attend rigorous lessons from seven in the morning, and to lead lives of religious observance and virtue. When his children strayed from George's own principles of righteousness, as his sons did as young adults, he was dismayed and disappointed.

The King disliked Fox intensely, for his politics as well as his character; he thought Fox was unprincipled and a bad influence on the Prince of Wales. George III was distressed at having to appoint ministers not of his liking, but the Portland ministry quickly built up a majority in the House of Commons, and could not be displaced easily. He was further dismayed when the government introduced the India Bill, which proposed to reform the government of India by transferring political power from the East India Company to Parliamentary commissioners. Although the King actually favoured greater control over the Company, the proposed commissioners were all political allies of Fox. Immediately after the House of Commons passed it, George authorised Lord Temple to inform the House of Lords that he would regard any peer who voted for the bill as his enemy. The bill was rejected by the Lords; three days later, the Portland ministry was dismissed, and william Pitt the Younger was appointed Prime Minister, with Temple as his Secretary of State. On 17 December 1783, Parliament voted in favour of a motion condemning the influence of the monarch in parliamentary voting as a "high crime" and Temple was forced to resign. Temple's departure destabilised the government, and three months later the government lost its majority and Parliament was dissolved; the subsequent election gave Pitt a firm mandate.

The French Revolution of 1789, in which the French monarchy had been overthrown, worried many British landowners. France declared war on Great Britain in 1793; in the war attempt, George allowed Pitt to increase taxes, raise armies, and suspend the right of habeas corpus. The First Coalition to oppose revolutionary France, which included Austria, Prussia, and Spain, broke up in 1795 when Prussia and Spain made separate peace with France. The Second Coalition, which included Austria, Russia, and the Ottoman Empire, was defeated in 1800. Only Great Britain was left fighting Napoleon Bonaparte, the First Consul of the French Republic.

His life and with it his reign, which were longer than those of any of his predecessors, were marked by a series of military conflicts involving his kingdoms, much of the rest of Europe, and places farther afield in Africa, the Americas and Asia. Early in his reign, Great Britain defeated France in the Seven Years' War, becoming the dominant European power in North America and India. However, many of Britain's American colonies were soon lost in the American War of Independence. Further wars against revolutionary and Napoleonic France from 1793 concluded in the defeat of Napoleon at the Battle of Waterloo in 1815.

Following the Acts of Union 1800, the royal arms were amended, dropping the French quartering. They became: Quarterly, I and IV England; II Scotland; III Ireland; overall an escutcheon of Hanover surmounted by an electoral bonnet. In 1816, after the Electorate of Hanover became a kingdom, the electoral bonnet was changed to a crown.

In Great Britain, George III used the official style "George the Third, by the Grace of God, King of Great Britain, France, and Ireland, Defender of the Faith, and so forth". In 1801, when Great Britain united with Ireland, he dropped the title of king of France, which had been used for every English monarch since Edward III's claim to the French throne in the medieval period. His style became "George the Third, by the Grace of God, of the United Kingdom of Great Britain and Ireland King, Defender of the Faith."

George did not consider the peace with France as real; in his view it was an "experiment". In 1803, the war resumed but public opinion distrusted Addington to lead the nation in war, and instead favoured Pitt. An invasion of England by Napoleon seemed imminent, and a massive volunteer movement arose to defend England against the French. George's review of 27,000 volunteers in Hyde Park, London, on 26 and 28 October 1803 and at the height of the invasion scare, attracted an estimated 500,000 spectators on each day. The Times said, "The enthusiasm of the multitude was beyond all expression." A courtier wrote on 13 November that, "The King is really prepared to take the field in case of attack, his beds are ready and he can move at half an hour's warning." George wrote to his friend Bishop Hurd, "We are here in daily expectation that Bonaparte will attempt his threatened invasion ... Should his troops effect a landing, I shall certainly put myself at the head of mine, and my other armed subjects, to repel them." After Admiral Lord Nelson's famous naval victory at the Battle of Trafalgar, the possibility of invasion was extinguished.

In 1804, George's recurrent illness returned; after his recovery, Addington resigned and Pitt regained power. Pitt sought to appoint Fox to his ministry, but George III refused. Lord Grenville perceived an injustice to Fox, and refused to join the new ministry. Pitt concentrated on forming a coalition with Austria, Russia, and Sweden. This Third Coalition, however, met the same fate as the First and Second Coalitions, collapsing in 1805. The setbacks in Europe took a toll on Pitt's health and he died in 1806, reopening the question of who should serve in the ministry. Lord Grenville became Prime Minister, and his "Ministry of All the Talents" included Fox. The King was conciliatory towards Fox, after being forced to capitulate over his appointment. After Fox's death in September 1806, the King and ministry were in open conflict. To boost recruitment, the ministry proposed a measure in February 1807 whereby Roman Catholics would be allowed to serve in all ranks of the Armed Forces. George instructed them not only to drop the measure, but also to agree never to set up such a measure again. The ministers agreed to drop the measure then pending, but refused to bind themselves in the Future. They were dismissed and replaced by the Duke of Portland as the nominal Prime Minister, with actual power being held by the Chancellor of the Exchequer, Spencer Perceval. Parliament was dissolved, and the subsequent election gave the ministry a strong majority in the House of Commons. George III made no further major political decisions during his reign; the replacement of the Duke of Portland by Perceval in 1809 was of little actual significance.

In Germany, he was "Duke of Brunswick and Lüneburg, Archtreasurer and Prince-elector of the Holy Roman Empire" until the end of the empire in 1806. He then continued as duke until the Congress of Vienna declared him "King of Hanover" in 1814.

In late 1810, at the height of his popularity, already virtually blind with cataracts and in pain from rheumatism, George became dangerously ill. In his view the malady had been triggered by stress over the death of his youngest and favourite daughter, Princess Amelia. The Princess's nurse reported that "the scenes of distress and crying every day ... were melancholy beyond description." He accepted the need for the Regency Act of 1811, and the Prince of Wales acted as Regent for the remainder of George III's life. Despite signs of a recovery in May 1811, by the end of the year George had become permanently insane and lived in seclusion at Windsor Castle until his death.

Prime Minister Spencer Perceval was assassinated in 1812 and was replaced by Lord Liverpool. Liverpool oversaw British victory in the Napoleonic Wars. The subsequent Congress of Vienna led to significant territorial gains for Hanover, which was upgraded from an electorate to a kingdom.

Meanwhile, George's health deteriorated. He developed dementia, and became completely blind and increasingly deaf. He was incapable of knowing or understanding either that he was declared King of Hanover in 1814, or that his wife died in 1818. At Christmas 1819, he spoke nonsense for 58 hours, and for the last few weeks of his life was unable to walk. He died at Windsor Castle at 8:38 pm on 29 January 1820, six days after the death of his fourth son, the Duke of Kent. His favourite son, Frederick, Duke of York, was with him. George III was buried on 16 February in St George's Chapel, Windsor Castle.

George III was dubbed "Farmer George" by satirists, at first to mock his interest in mundane matters rather than politics, but later to contrast his homely thrift with his son's grandiosity and to portray him as a man of the people. Under George III, the British Agricultural Revolution reached its peak and great advances were made in fields such as science and industry. There was unprecedented growth in the rural population, which in turn provided much of the workforce for the concurrent Industrial Revolution. George's collection of mathematical and scientific instruments is now owned by King's College London but housed in the Science Museum, London, to which it has been on long-term loan since 1927. He had the King's Observatory built in Richmond-upon-Thames for his own observations of the 1769 transit of Venus. When william Herschel discovered Uranus in 1781, he at first named it Georgium Sidus (George's Star) after the King, who later funded the construction and maintenance of Herschel's 1785 40-foot telescope, which was the biggest ever built at the time.

By this time George's health was deteriorating. He had a mental illness, characterised by acute mania, which was possibly a symptom of the genetic disease porphyria, although this has been questioned. A study of samples of the King's hair published in 2005 revealed high levels of arsenic, a possible trigger for the disease. The source of the arsenic is not known, but it could have been a component of medicines or cosmetics. The King may have had a brief episode of disease in 1765, but a longer episode began in the summer of 1788. At the end of the parliamentary session, he went to Cheltenham Spa to recuperate. It was the furthest he had ever been from London—just short of 100 miles (150 km)—but his condition worsened. In November he became seriously deranged, sometimes speaking for many hours without pause, causing him to foam at the mouth and making his voice hoarse. His doctors were largely at a loss to explain his illness, and spurious stories about his condition spread, such as the claim that he shook hands with a tree in the mistaken belief that it was the King of Prussia. Treatment for mental illness was primitive by modern standards, and the King's doctors, who included Francis Willis, treated the King by forcibly restraining him until he was calm, or applying caustic poultices to draw out "evil humours".