Cromwell declared to Archbishop of Canterbury Thomas Cranmer that he had been a "ruffian… in his young days". As a youth, he left his family in Putney, and crossed the Channel to the continent. Accounts of his activities in France, Italy and the Low Countries are sketchy and contradictory. It is alleged that he first became a mercenary, and marched with the French army to Italy, where he fought in the battle of Garigliano on 28 December 1503. While in Italy, he entered Service in the household of the Florentine banker Francesco Frescobaldi.

Later, he visited leading mercantile centres in the Low Countries, living among the English merchants and developing a network of contacts while learning several languages. At some point he returned to Italy. The records of the English Hospital in Rome indicate that he stayed there in June 1514, while documents in the Vatican Archives suggest that he was an agent for the Archbishop of York, Cardinal Christopher Bainbridge, and handled English ecclesiastical issues before the Roman Rota.

At some time during these years, Cromwell returned to England, where around 1515 he married Elizabeth Wyckes (d. 1529). She was the widow of Thomas Williams, a Yeoman of the Guard, and the daughter of a Putney shearman, Henry Wykes, who had served as a gentleman usher to King Henry VII. The couple had three children:

From around 1516 to 1530, Cromwell was a member of the household of Lord Chancellor Thomas Cardinal Wolsey. He was one of Wolsey's council by 1519, and his secretary by 1529. In the mid-1520s, Cromwell assisted in the dissolution of nearly thirty monasteries to raise funds for Wolsey to found The King's School, Ipswich (1528), and Cardinal College, in Oxford (1529). In 1526, Wolsey appointed Cromwell a member of his council; by 1529, Cromwell was one of Wolsey's most senior and trusted advisers. By the end of October of that year, however, Wolsey had fallen from power. Cromwell had made enemies by aiding Wolsey to suppress the monasteries, but was determined not to fall with his master, as he told George Cavendish, then a Gentleman Usher and later Wolsey's biographer:

In 1517, and again in 1518, Cromwell led an embassy to Rome to obtain from Pope Leo X a papal bull for the reinstatement of Indulgences for the town of Boston, Lincolnshire.

By 1520, Cromwell was firmly established in London mercantile and legal circles. In 1523, he obtained a seat in the House of Commons as a Burgess, though the constituency he represented has not been identified. After Parliament had been dissolved, Cromwell wrote a letter to a friend, jesting about the session's lack of productivity:

In 1524, he was elected a member of Gray's Inn.

From 1527, Henry VIII had sought to have his marriage to Queen Catherine of Aragon annulled, so that he could lawfully marry Anne Boleyn. At the centre of the campaign to secure the annulment was the emerging doctrine of royal supremacy over the church. By the autumn of 1531, Cromwell had taken control of the supervision of the king's legal and parliamentary affairs, working closely with Thomas Audley, and had joined the inner circle of the Council. By the following spring, he had begun to exert influence over elections to the House of Commons.

Cromwell successfully overcame the Shadow cast over his career by Wolsey's downfall. By November 1529, he had secured a seat in Parliament as a member for Taunton and was reported to be in favour with the King. At some point during the closing weeks of 1530, the King appointed him to the Privy Council. Cromwell held numerous offices during his career in the King's Service, including:

Although Cromwell always maintained a primarily political outlook on general affairs, there is consensus among scholars that at least while he held power he was a Protestant, with a Lutheran mindset. For him, the Henrician Reformation was certainly more than a jurisdictional revolution masquerading in religious garb. For instance, in the mid-1530s, he promoted Protestant ideas to forge an alliance with German Lutheran states, but his support for the Protestant cause is too general to be accurately explained in narrow political terms.

The king's gratitude to Cromwell was expressed in a grant of the lordship of Romney in Newport, Wales, and appointment to three relatively minor offices: Master of the Jewels on 14 April 1532, Clerk of the Hanaper on 16 July, and Chancellor of the Exchequer on 12 April 1533. None of these offices afforded much income, but the appointments were an indication of royal favour, and gave Cromwell a position in three major institutions of government: the royal household, the Chancery, and the Exchequer.

The parliamentary session began on 4 February, and Cromwell introduced a new bill restricting the right to make appeals to Rome. On 30 March, Cranmer was consecrated Archbishop of Canterbury, and Convocation immediately declared the king's marriage to Catherine unlawful. In the first week of April 1533, Parliament passed Cromwell's bill into law, as the Act in Restraint of Appeals, ensuring that any verdict concerning the king's marriage could not be challenged in Rome. On 11 April, Archbishop Cranmer sent the King a pro forma challenge to the validity of his marriage to Catherine. A formal trial began on 10 May 1533 in Dunstable and on 23 May the Archbishop pronounced sentence, declaring the marriage illegal. Five days later he pronounced the King's marriage to Anne to be lawful, and on 1 June, she was crowned queen.

In April 1534, Henry confirmed Cromwell as his principal secretary and chief minister, a position which he had held for some time in all but name. Cromwell immediately took steps to enforce the legislation just passed by Parliament. Before the members of both houses returned home on 30 March, they were required to swear an oath accepting the Act of Succession, and all the King's subjects were now required to swear to the legitimacy of the marriage and, by implication, to accept the King's new powers and the break from Rome. On 13 April, the London clergy accepted the oath. On the same day, the commissioners offered it to Sir Thomas More and John Fisher, Bishop of Rochester, both of whom refused it. More was taken into custody on the same day and was moved to the Tower of London on 17 April. Fisher joined him there four days later.

In 1535 Cromwell succeeded in having clearly identified reformers, such as Hugh Latimer, Edward Foxe and Nicholas Shaxton appointed to the episcopacy. He encouraged and supported the work of reformers, such as Robert Barnes and obtained the license to publish the Matthew's Bible, provided significant funding for the printing of this English translation of the Bible and sent one to all parishes in England. By 1538, it was compulsory for all churches to own a Bible, in accordance with Cromwell's injunctions. The revised version, the Great Bible was widely available by 1539 and included a picture of Henry VIII, Thomas Cranmer and Cromwell on the title page.

During Cromwell's years in power, he skilfully managed Crown finances and extended royal authority. In 1536, he established the Court of Augmentations to handle the massive windfall to the royal coffers from the Dissolution of the Monasteries. Two other important financial institutions, the Court of Wards and the Court of First Fruits and Tenths, owed their existence to him, although they were not set up until after his death. He strengthened royal authority in the north of England, through reform of the Council of the North, extended royal power and introduced Protestantism in Ireland, and was the Architect of the Laws in Wales Acts 1535 and 1542, which promoted stability and gained acceptance for the royal supremacy in Wales. He also introduced important social and economic reforms in England in the 1530s, including action against enclosures, the promotion of English cloth exports and the poor relief legislation of 1536.

Queen Jane had died in 1537, less than two weeks after the birth of her only child, the Future Edward VI. In early October 1539, the King finally accepted Cromwell's suggestion that he should marry Anne of Cleves, the sister of Duke Wilhelm of Cleves, partly on the basis of a portrait which Hans Holbein had painted of her. On 27 December, Anne of Cleves arrived at Dover. On New Year's Day 1540, the King met her at Rochester and was immediately repelled by her physically: "I like her not!" The wedding ceremony took place on 6 January at Greenwich, but the marriage was not consummated. Henry said that he found it impossible to enjoy conjugal relations with a woman whom he found so unattractive.

On 17 December 1538, the Inquisitor-General of France forbade the printing of Miles Coverdale's Great Bible. Cromwell persuaded the King of France to release the unfinished books so that printing could continue in England. The first edition was finally available in April 1539. The publication of the Great Bible was one of Cromwell's principal achievements, the first authoritative version in English.

The King, however, continued to resist further Reformation measures. A Parliamentary committee was established to examine doctrine, and the Duke of Norfolk presented six questions on 16 May 1539 for the House to consider, which were duly passed as the Act of Six Articles shortly before the session ended on 28 June. The Six Articles reaffirmed a traditional view of the Mass, the Sacraments, and the priesthood.

When Cromwell fell from favour in 1540, his alleged support for Anabaptism was cited. Although the charge was spurious, the fact that it was levelled at all demonstrates the reputation for evangelical sympathies Cromwell had developed.

Henry came to regret Cromwell's killing and later accused his ministers of bringing about Cromwell's downfall by "pretexts" and "false accusations". On 3 March 1541, the French Ambassador, Charles de Marillac, reported in a letter that the King was now said to be lamenting that,

Little is known about Cromwell's early life. It is believed that he was born at the top of Putney Hill, on the edge of Putney Heath. In 1878, his birthplace was still of note:

Until the 1950s, historians discounted Cromwell's role, calling him a doctrinaire hack who was little more than the agent of the despotic King Henry VIII, as is borne out by the 1911 Encyclopædia Britannica, when it says, "his power has been overrated". Geoffrey Elton, however, featured him as the central figure in the Tudor revolution in government in The Tudor Revolution (1953). Elton portrayed Cromwell as the presiding genius, much more so than the king, handling the break with Rome and creating the laws and administrative procedures that reshaped post-Reformation England. Elton wrote that Cromwell had been responsible for translating royal supremacy into parliamentary terms, creating powerful new organs of government to take charge of Church lands, and largely removing the medieval features of central government.

Subsequent historians have agreed with Elton as to Cromwell's importance, though not with his claims of "revolution". Leithead (2004) wrote, "Against significant opposition he secured acceptance of the king's new powers, created a more united and more easily governable kingdom, and provided the crown, at least temporarily, with a very significant landed endowment."

Cromwell has been portrayed in a number of plays, feature films, and television miniseries, usually as a villainous character. More recently, however, Hilary Mantel's two Man Booker Prize-winning novels Wolf Hall (2009) and Bring up the Bodies (2012) have sought to show him in a more sympathetic light, stressing his family affections, genuine respect for Cardinal Wolsey, zeal for the Reformation, and support for a limited degree of social reform.