Canning was born into an Anglo-Irish family at his parents' home in Queen Anne Street, Marylebone, London. Canning described himself as "an Irishman born in London". His father, George Canning, Sr., of Garvagh, County Londonderry, Ireland, was a gentleman of limited means, a failed wine merchant and Lawyer, who renounced his right to inherit the family estate in exchange for payment of his substantial debts. George Sr. eventually abandoned the family and died in poverty on 11 April 1771, his son's first birthday, in London. Canning's mother, Mary Anne Costello, took work as a stage Actress, a profession not considered respectable at the time. Indeed, when in 1827 it looked as if Canning would become Prime Minister, Lord Grey remarked that "the son of an Actress is, ipso facto, disqualified from becoming Prime Minister".

Stratford Canning was a Whig and would introduce his nephew in the 1780s to prominent Whigs such as Charles James Fox, Edmund Burke, and Richard Brinsley Sheridan. George Canning's friendship with Sheridan would last for the remainder of Sheridan's life.

Canning struck up friendships with the Future Lord Liverpool as well as with Granville Leveson-Gower and John Hookham Frere. In 1789 he won a prize for his Latin poem The Pilgrimage to Mecca which he recited in Oxford Theatre. Canning began practising law after receiving his BA from Oxford in the summer of 1791, but he wished to enter politics.

George Canning's impoverished background and limited financial resources, however, made unlikely a bright political Future in a Whig party whose political ranks were led mostly by members of the wealthy landed aristocracy in league with the newly rich industrialist classes. Regardless, along with Whigs such as Burke, Canning himself would become considerably more conservative in the early 1790s after witnessing the excessive radicalism of the French Revolution. "The political reaction which then followed swept the young man to the opposite extreme; and his vehemence for monarchy and the Tories gave point to a Whig sarcasm,—that men had often turned their coats, but this was the first time a boy had turned his jacket."

So when Canning decided to enter politics he sought and received the patronage of the leader of the "Tory" group, william Pitt the Younger. In 1793, thanks to the help of Pitt, Canning became a member of parliament for Newtown on the Isle of Wight, a rotten borough. In 1796, he changed seats to a different rotten borough, Wendover in Buckinghamshire. He was elected to represent several constituencies during his parliamentary career.

On 2 November 1795, Canning received his first ministerial post: Under Secretary of State for Foreign Affairs. In this post he proved a strong supporter of Pitt, often taking his side in disputes with the Foreign Secretary, Lord Grenville. At the end of 1798 Canning responded to a resolution by George Tierney MP for peace negotiations with France:

Canning was involved in the founding of the Anti-Jacobin, a newspaper which was published on every Monday from 20 November 1797 to 9 July 1798. Its purpose was to support the government and condemn revolutionary doctrines through news and poetry, much of it written by Canning. Canning's poetry satirised and ridiculed Jacobin poetry. Before the appearance of the Anti-Jacobin all the eloquence (except for Burke's) and all the wit and ridicule had been on the side of Fox and Sheridan. Canning and his friends changed this. A young Whig, william Lamb (the Future Lord Melbourne, Prime Minister) wrote an 'Epistle to the Editors of the Anti-Jacobin', which attacked Canning:

In 1799 Canning became a Commissioner of the Board of Control for India. Canning wrote on 16 April: "Here I am immersed in papers, of which I do not yet comprehend three words in succession; but I shall get at their meaning by degrees and at my leisure. No such hard work here as at my former office. No attendance but when I like it, when there are interesting letters received from India (as is now the case) or to be sent out there".

Canning married Joan Scott (later 1st Viscountess Canning) (1776–1837) on 8 July 1800, with John Hookham Frere and william Pitt the Younger as witnesses.

Canning disliked being out of office, and wrote on to John Hookham Frere in summer 1801: "But the thought will obtrude itself now and then that I am not where I should be – non-hoc pollicitus." He also claimed that Pitt had done "scrupulously and magnanimously right by everyone but me". At the end of September 1801 Canning wrote to Frere, saying of Pitt: "I do love him, and reverence him as I should a Father – but a Father should not sacrifice me, with my good will. Most heartily I forgive him, But he has to answer to himself, and to the country for much mischief that he has done and much that is still to do." Pitt wished for Canning to enter Henry Addington's government, a move which Canning looked on as a horrible dilemma but in the end he turned the offer down.

At a dinner to celebrate Pitt's birthday in 1802, Canning wrote the song ‘The Pilot that Weathered the Storm’, performed by a tenor from Drury Lane, Charles Dignum:

Canning approved of the declaration of war against France on 18 May 1803. Canning was angered by Pitt's Desire not to proactively work to turn out the ministry but support the ministry when it adopted sound policies. However, in 1804, to Canning's delight, Pitt began to work against the Addington government. After Pitt delivered a stinging attack on the government's defence measures on 25 April, Canning launched his own attack on Addington, which made Addington furious. On 30 April Lord Eldon, the Lord Chancellor, asked Pitt to submit a new administration to the King.

Canning returned to office in 1804 with Pitt, becoming Treasurer of the Navy. In 1805 he offered Pitt his resignation after Addington was given a seat in the Cabinet. He wrote to Lady Hester to say he felt humiliated that Addington was a minister "and I am – nothing. I cannot help it, I cannot face the House of Commons or walk the streets in this state of things, as I am". After reading this letter Pitt summoned Canning to London for a meeting, where he told him that if he resigned it would open a permanent breach between the two of them as it would cast a slur on his conduct. He offered Canning the office of Chief Secretary for Ireland but he refused on the grounds that this would look like he was being got out of the way. Canning eventually decided not to resign and wrote that "I am resolved to "sink or swim" with Pitt, though he has tied himself to such sinking company. God forgive him". Canning left office with the death of Pitt; he was not offered a place in Lord Grenville's administration.

During his first period in the Foreign Office (1807–09) Canning became deeply involved in the affairs of Spain, Portugal and Latin America. In his second term of office he sought to prevent South America from coming into the French sphere of influence, and in this he was successful. He helped guarantee the independence of Brazil and the Spanish colonies, thereby acting in support of the Monroe Doctrine and aiding British merchants open new markets across South and Central America.

On 3 February 1808 the opposition leader George Ponsonby requested the publication of all information on the strength and battle-worthiness of the Danish fleet sent by the British envoy at Copenhagen. Canning replied with a speech nearly three hours long, described by Lord Palmerston as "so powerful that it gave a decisive turn to the debate". Lord Grey said his speech was "eloquent and powerful" but that he had never heard such "audacious misrepresentation" and "positive falsehood". On 2 March the opposition moved a vote of censure over Copenhagen, defeated by 224 votes to 64 after Canning gave a speech, in the words of Lord Glenbervie, so "very witty, very eloquent and very able".

Castlereagh discovered the deal in September 1809 and challenged Canning to a duel. Canning accepted the challenge and it was fought on 21 September 1809 on Putney Heath. Canning, who had never before fired a pistol, widely missed his mark. Castlereagh, who was regarded as one of the best shots of his day, wounded his opponent in the thigh. There was much outrage that two cabinet ministers had resorted to such a method. Shortly afterwards the ailing Portland resigned as Prime Minister, and Canning offered himself to George III as a potential successor. However, the King appointed Spencer Perceval instead, and Canning left office once more. He did take consolation, though, in the fact that Castlereagh also stood down.

Upon Perceval's assassination in 1812, the new Prime Minister, Lord Liverpool, offered Canning the position of Foreign Secretary once more. Canning refused, as he also wished to be Leader of the House of Commons and was reluctant to serve in any government with Castlereagh.

In 1814 he became the British Ambassador to Portugal, returning the following year. He received several further offers of office from Liverpool.

Canning was the arch-enemy of the Concert of Europe system set up by the conservative powers at the Congress of Vienna in 1815. Hayes says that in terms of foreign affairs:

In 1816 he became President of the Board of Control.

Canning resigned from office once more in 1820, in opposition to the treatment of Queen Caroline, estranged wife of the new King George IV. Public opinion strongly supported the Queen and thereby Canning was strengthened.

On 16 March 1821 Canning spoke in favour of william Plunket's Catholic Emancipation Bill. Liverpool wished to have Canning back in the Cabinet but the King was strongly hostile to him due to his actions over the Caroline affair. The King would only allow Canning back into the Cabinet if he did not have to deal personally with him. This required the office of Governor-General of India. After deliberating on whether to accept, Canning initially declined the offer but then accepted it. On 25 April he spoke in the Commons against Lord John Russell's motion for parliamentary reform and a few days later Canning moved for leave to introduce a measure of Catholic Emancipation (for lifting the exclusion of Catholics from the House of Lords). This passed the Commons but was rejected by the Lords.

In August 1822, Castlereagh committed suicide. Instead of going to India, Canning succeeded him as both Foreign Secretary and Leader of the House of Commons. He gave support to the growing campaign for the abolition of slavery. Canning continued many of Castlereagh's foreign policies, such as the view that the powers of Europe (Russia, France, etc.) should not be allowed to meddle in the affairs of other states. This policy enhanced public opinion of Canning as a liberal. He also prevented the United States from opening trade with the British West Indies.

In 1825 Mexico, Argentina and Colombia were recognised by means of the ratification of commercial treaties with Britain. In November 1825 the first minister from a Latin American state, Colombia, was officially received in London. "Spanish America is free," Canning declared, "and if we do not mismanage our affairs she is English ... the New World established and if we do not throw it away, ours." Also in 1825, Portugal recognised Brazil (thanks to Canning's efforts, and in return for a preferential commercial treaty), less than three years after Brazil's declaration of independence.

In 1826 he was elected a Fellow of the Royal Society.

However, Canning's health by this time was in steep decline: at the funeral of Frederick, Duke of York, which was held during a January night at St George's Chapel, Windsor Castle, he became so ill that it was thought he might not recover. He died later that year, on 8 August 1827, in the very same room where Charles James Fox met his own end, 21 years earlier. To this day Canning's total period in office remains the shortest of any Prime Minister of the United Kingdom, a mere 119 days. He is buried in Westminster Abbey.

Canning has come to be regarded as a "lost leader", with much speculation about what his legacy could have been had he lived. His government of Tories and Whigs continued for a few months under Lord Goderich but fell apart in early 1828. It was succeeded by a government under the Duke of Wellington, which initially included some Canningites but soon became mostly "High Tory" when many of the Canningites drifted over to the Whigs. Wellington's administration would soon go down in defeat as well. Some historians have seen the revival of the Tories from the 1830s onwards, in the form of the Conservative Party, as the overcoming of the divisions of 1827. What would have been the course of events had Canning lived is highly speculative.

Britain had a strong interest in ensuring the demise of Spanish colonialism, and to open the newly independent Latin American colonies to its trade. The Latin Americans received a certain amount of unofficial aid – arms and volunteers – from outside, but no outside official help at any stage from Britain or any other power. Britain refused to aid Spain and opposed any outside intervention on behalf of Spain by other powers. The Royal Navy was a decisive factor in the struggle for independence of certain Latin American countries.