Edward was born on 12 October 1537 in his mother's room inside Hampton Court Palace, in Middlesex. He was the son of King Henry VIII by his third wife, Jane Seymour. Throughout the realm, the people greeted the birth of a male heir, "whom we hungered for so long", with joy and relief. Te Deums were sung in churches, bonfires lit, and "their was shott at the Tower that night above two thousand gonnes". Queen Jane, appearing to recover quickly from the birth, sent out personally signed letters announcing the birth of "a Prince, conceived in most lawful matrimony between my Lord the King's Majesty and us". Edward was christened on 15 October, with his half-sisters, the 21-year-old Lady Mary as godmother and the 4-year-old Lady Elizabeth carrying the chrisom; and the Garter King of Arms proclaimed him as Duke of Cornwall and Earl of Chester. The Queen, however, fell ill on 23 October from presumed postnatal complications, and died the following night. Henry VIII wrote to Francis I of France that "Divine Providence ... hath mingled my joy with bitterness of the death of her who brought me this happiness".

Edward was a healthy baby who suckled strongly from the outset. His father was delighted with him; in May 1538, Henry was observed "dallying with him in his arms ... and so holding him in a window to the sight and great comfort of the people". That September, the Lord Chancellor, Lord Audley, reported Edward's rapid growth and vigour; and other accounts describe him as a tall and merry child. The tradition that Edward VI was a sickly boy has been challenged by more recent historians. At the age of four, he fell ill with a life-threatening "quartan fever", but, despite occasional illnesses and poor eyesight, he enjoyed generally good health until the last six months of his life.

In his document Edward provided, in case of "lack of issue of my body", for the succession of male heirs only, that is, Jane Grey's mother's male heirs, Jane's, or her sisters'. As his death approached and possibly persuaded by Northumberland, he altered the wording so that Jane and her sisters themselves should be able to succeed. Yet Edward conceded Jane's right only as an exception to male rule, demanded by reality, an Example not to be followed if Jane or her sisters had only daughters. In the final document both Mary and Elizabeth were excluded because of bastardy; since both had been declared bastards under Henry VIII and never made legitimate again, this reason could be advanced for both sisters. The provisions to alter the succession directly contravened Henry VIII's Third Succession Act of 1543 and have been described as bizarre and illogical.

Somerset's only undoubted skill was as a soldier, which he had proven on expeditions to Scotland and in the defence of Boulogne-sur-Mer in 1546. From the first, his main interest as Protector was the war against Scotland. After a crushing victory at the Battle of Pinkie Cleugh in September 1547, he set up a network of garrisons in Scotland, stretching as far north as Dundee. His initial successes, however, were followed by a loss of direction, as his aim of uniting the realms through conquest became increasingly unrealistic. The Scots allied with France, who sent reinforcements for the defence of Edinburgh in 1548. The Queen of Scots was moved to France, where she was betrothed to the Dauphin. The cost of maintaining the Protector's massive armies and his permanent garrisons in Scotland also placed an unsustainable burden on the royal finances. A French attack on Boulogne in August 1549 at last forced Somerset to begin a withdrawal from Scotland.

Somerset's appointment was in keeping with historical precedent, and his eligibility for the role was reinforced by his military successes in Scotland and France. In March 1547, he secured letters patent from King Edward granting him the almost monarchical right to appoint members to the Privy Council himself and to consult them only when he wished. In the words of Historian Geoffrey Elton, "from that moment his autocratic system was complete". He proceeded to rule largely by proclamation, calling on the Privy Council to do little more than rubber-stamp his decisions.

The same justification for outbreaks of unrest was voiced throughout the country, not only in Norfolk and the west. The origin of the popular view of Somerset as sympathetic to the rebel cause lies partly in his series of sometimes liberal, often contradictory, proclamations, and partly in the uncoordinated activities of the commissions he sent out in 1548 and 1549 to investigate grievances about loss of tillage, encroachment of large sheep flocks on Common land, and similar issues. Somerset's commissions were led by an evangelical M.P. called John Hales, whose socially liberal rhetoric linked the issue of enclosure with Reformation theology and the notion of a godly commonwealth. Local groups often assumed that the findings of these commissions entitled them to act against offending landlords themselves. King Edward wrote in his Chronicle that the 1549 risings began "because certain commissions were sent down to pluck down enclosures".

Historians contrast the efficiency of Somerset's takeover of power, in which they detect the organising skills of allies such as Paget, the "master of practices", with the subsequent ineptitude of his rule. By autumn 1549, his costly wars had lost momentum, the crown faced financial ruin, and riots and rebellions had broken out around the country. Until recent decades, Somerset's reputation with historians was high, in view of his many proclamations that appeared to back the Common people against a rapacious landowning class. More recently, however, he has often been portrayed as an arrogant and aloof ruler, lacking in political and administrative skills.

Although Edward reigned for only six years and died at the age of 15, his reign made a lasting contribution to the English Reformation and the structure of the Church of England. The last decade of Henry VIII's reign had seen a partial stalling of the Reformation, a drifting back to more conservative values. By contrast, Edward's reign saw radical progress in the Reformation. In those six years, the Church transferred from an essentially Roman Catholic liturgy and structure to one that is usually identified as Protestant. In particular, the introduction of the Book of Common Prayer, the Ordinal of 1550, and Cranmer's Forty-two Articles formed the basis for English Church practices that continue to this day. Edward himself fully approved these changes, and though they were the work of reformers such as Thomas Cranmer, Hugh Latimer, and Nicholas Ridley, backed by Edward's determinedly evangelical Council, the fact of the king's religion was a catalyst in the acceleration of the Reformation during his reign.

After 1551, the Reformation advanced further, with the approval and encouragement of Edward, who began to exert more personal influence in his role as Supreme Head of the church. The new changes were also a response to criticism from such reformers as John Hooper, Bishop of Gloucester, and the Scot John Knox, who was employed as a minister in Newcastle upon Tyne under the Duke of Northumberland and whose preaching at court prompted the king to oppose kneeling at communion. Cranmer was also influenced by the views of the continental reformer Martin Bucer, who died in England in 1551, by Peter Martyr, who was teaching at Oxford, and by other foreign Theologians. The progress of the Reformation was further speeded by the consecration of more reformers as bishops. In the winter of 1551–52, Cranmer rewrote the Book of Common Prayer in less ambiguous reformist terms, revised canon law, and prepared a doctrinal statement, the Forty-two Articles, to clarify the practice of the reformed religion, particularly in the divisive matter of the communion Service. Cranmer's formulation of the reformed religion, finally divesting the communion Service of any notion of the real presence of God in the bread and the wine, effectively abolished the mass. According to Elton, the publication of Cranmer's revised prayer book in 1552, supported by a second Act of Uniformity, "marked the arrival of the English Church at Protestantism". The prayer book of 1552 remains the foundation of the Church of England's services. However, Cranmer was unable to implement all these reforms once it became clear in spring 1553 that King Edward, upon whom the whole Reformation in England depended, was dying.

Working with william Paulet and Walter Mildmay, Warwick tackled the disastrous state of the kingdom's finances. However, his regime first succumbed to the temptations of a quick profit by further debasing the coinage. The economic disaster that resulted caused Warwick to hand the initiative to the expert Thomas Gresham. By 1552, confidence in the coinage was restored, prices fell, and trade at last improved. Though a full economic recovery was not achieved until Elizabeth's reign, its origins lay in the Duke of Northumberland's policies. The regime also cracked down on widespread embezzlement of government finances, and carried out a thorough review of revenue collection practices, which has been called "one of the more remarkable achievements of Tudor administration".

Edward made his final appearance in public on 1 July, when he showed himself at his window in Greenwich Palace, horrifying those who saw him by his "thin and wasted" condition. During the next two days, large crowds arrived hoping to see the king again, but on 3 July, they were told that the weather was too chilly for him to appear. Edward died at the age of 15 at Greenwich Palace at 8pm on 6 July 1553. According to John Foxe's legendary account of his death, his last words were: "I am faint; Lord have mercy upon me, and take my spirit". He was buried in the Henry VII Lady Chapel at Westminster Abbey on 8 August 1553, with reformed rites performed by Thomas Cranmer. The procession was led by "a grett company of chylderyn in ther surples" and watched by Londoners "wepyng and lamenting"; the funeral chariot, draped in cloth of gold, was topped by an effigy of Edward, with crown, sceptre, and garter. Edward's burial place was unmarked until as late as 1966, when an inscribed stone was laid in the chapel floor by Christ's Hospital school to commemorate their founder. The inscription reads as follows: "In Memory Of King Edward VI Buried In This Chapel This Stone Was Placed Here By Christ's Hospital In Thanksgiving For Their Founder 7 October 1966".

It now dawned on the Privy Council that it had made a terrible mistake. Led by the Earl of Arundel and the Earl of Pembroke, on 19 July the Council publicly proclaimed Mary as queen; Jane's nine-day reign came to an end. The proclamation triggered wild rejoicing throughout London. Stranded in Cambridge, Northumberland proclaimed Mary himself—as he had been commanded to do by a letter from the Council. william Paget and the Earl of Arundel rode to Framlingham to beg Mary's pardon, and Arundel arrested Northumberland on 24 July. Northumberland was beheaded on 22 August, shortly after renouncing Protestantism. His recantation dismayed his daughter-in-law, Jane, who followed him to the scaffold on 12 February 1554, after her father's involvement in Wyatt's rebellion.

On Mary's death in 1558, the English Reformation resumed its course, and most of the reforms instituted during Edward's reign were reinstated in the Elizabethan Religious Settlement. Queen Elizabeth replaced Mary's councillors and bishops with ex-Edwardians, such as william Cecil, Northumberland's former secretary, and Richard Cox, Edward's old tutor, who preached an anti-Catholic sermon at the opening of parliament in 1559. Parliament passed an Act of Uniformity the following spring that restored, with modifications, Cranmer's prayer book of 1552; and the Thirty-nine Articles of 1563 were largely based on Cranmer's Forty-two Articles. The theological developments of Edward's reign provided a vital source of reference for Elizabeth's religious policies, though the internationalism of the Edwardian Reformation was never revived.

For centuries, the attempt to alter the succession was mostly seen as a one-man-plot by the Duke of Northumberland. Since the 1970s, however, many historians have attributed the inception of the "devise" and the insistence on its implementation to the king's initiative. Diarmaid MacCulloch has made out Edward's "teenage dreams of founding an evangelical realm of Christ", while David Starkey has stated that "Edward had a couple of co-operators, but the driving will was his". Among other members of the Privy Chamber, Northumberland's intimate Sir John Gates has been suspected of suggesting to Edward to change his devise so that Lady Jane Grey herself—not just any sons of hers—could inherit the Crown. Whatever the degree of his contribution, Edward was convinced that his word was law and fully endorsed disinheriting his half-sisters: "barring Mary from the succession was a cause in which the young King believed."

Both Edward's sisters were attentive to their brother and often visited him – on one occasion, Elizabeth gave him a shirt "of her own working". Edward "took special content" in Mary's company, though he disapproved of her taste for foreign dances; "I love you most", he wrote to her in 1546. In 1543, Henry invited his children to spend Christmas with him, signalling his reconciliation with his daughters, whom he had previously illegitimised and disinherited. The following spring, he restored them to their place in the succession with a Third Succession Act, which also provided for a regency council during Edward's minority. This unaccustomed family harmony may have owed much to the influence of Henry's new wife, Catherine Parr, of whom Edward soon became fond. He called her his "most dear mother" and in September 1546 wrote to her: "I received so many benefits from you that my mind can hardly grasp them."

The cause of Edward VI's death is not certain. As with many royal deaths in the 16th century, rumours of poisoning abounded, but no evidence has been found to support these. The Duke of Northumberland, whose unpopularity was underlined by the events that followed Edward's death, was widely believed to have ordered the imagined poisoning. Another theory held that Edward had been poisoned by Catholics seeking to bring Mary to the throne. The surgeon who opened Edward's chest after his death found that "the disease whereof his majesty died was the disease of the lungs". The Venetian ambassador reported that Edward had died of consumption—in other words, tuberculosis—a diagnosis accepted by many historians. Skidmore believes that Edward contracted tuberculosis after a bout of measles and smallpox in 1552 that suppressed his natural immunity to the disease. Loach suggests instead that his symptoms were typical of acute bronchopneumonia, leading to a "suppurating pulmonary infection" or lung abscess, septicaemia, and kidney failure.