According to his friend, theologian Desiderius Erasmus of Rotterdam, More once seriously contemplated abandoning his legal career to become a monk. Between 1503 and 1504 More lived near the Carthusian monastery outside the walls of London and joined in the monks' spiritual exercises. Although he deeply admired their piety, More ultimately decided to remain a layman, standing for election to Parliament in 1504 and marrying the following year.

In 1504 More was elected to Parliament to represent Great Yarmouth, and in 1510 began representing London.

More married Jane Colt in 1505. She was five years younger than her husband, quiet and good-natured. Erasmus reported that More wanted to give his young wife a better education than she had previously received at home, and tutored her in music and literature. The couple had four children before Jane died in 1511: Margaret, Elizabeth, Cicely, and John.

From 1510, More served as one of the two undersheriffs of the City of London, a position of considerable responsibility in which he earned a reputation as an honest and effective public servant. More became Master of Requests in 1514, the same year in which he was appointed as a Privy Counsellor. After undertaking a diplomatic mission to the Holy Roman Emperor, Charles V, accompanying Thomas Wolsey, Cardinal Archbishop of York, to Calais and Bruges, More was knighted and made under-treasurer of the Exchequer in 1521.

Between 1512 and 1519 More worked on a History of King Richard III, which he never finished but which was published after his death. The History is a Renaissance biography, remarkable more for its literary skill and adherence to classical precepts than for its historical accuracy. Some consider it an attack on royal tyranny, rather than on Richard III himself or the House of York. More uses a more dramatic writing style than had been typical in medieval chronicles; Richard III is limned as an outstanding, archetypal tyrant - however, More was only seven years old when Richard III was killed at the Battle of Bosworth in 1485 so he had no first-hand in-depth knowledge of him.

More's best known and most controversial work, Utopia is a novel written in Latin. More completed and theologian Erasmus published the book in Leuven in 1516, but it was only translated into English and published in his native land in 1551 (16 years after his execution), and the 1684 translation became the most commonly cited. More (also a character in the book) and the narrator/traveller, Raphael Hythlodaeus (whose name alludes both to the healer archangel Raphael, and 'speaker of nonsense', the surname's Greek meaning), discuss modern ills in Antwerp, as well as describe the political arrangements of the imaginary island country of Utopia (a Greek pun on 'ou-topos' [no place] and 'eu-topos' [good place]) among themselves as well as to Pieter Gillis and Hieronymus van Busleyden. Utopia's original edition included a symmetrical "Utopian alphabet" omitted by later editions, but which may have been an early attempt or precursor of shorthand.

Most major humanists were prolific letter Writers, and Thomas More was no exception. As in the case of his friend Erasmus of Rotterdam, however, only a small portion of his correspondence (about 280 letters) survived. These include everything from personal letters to official government correspondence (mostly in English), letters to fellow humanist scholars (in Latin), several epistolary tracts, verse epistles, prefatory letters (some fictional) to several of More's own works, letters to More's children and their tutors (in Latin), and the so-called "prison-letters" (in English) which he exchanged with his oldest daughter Margaret while he was imprisoned in the Tower of London awaiting execution. More also engaged in controversies, most notably with the French poet Germain de Brie, which culminated in the publication of de Brie's Antimorus (1519). Erasmus intervened, however, and ended the dispute.

In 1520 the reformer Martin Luther published three works in quick succession: An Appeal to the Christian Nobility of the German Nation (Aug.), Concerning the Babylonish Captivity of the Church (Oct.), and On the Liberty of a Christian Man (Nov.). In these books, Luther set out his doctrine of salvation through grace alone, rejected certain Catholic practices, and attacked abuses and excesses within the Catholic Church. In 1521, Henry VIII formally responded to Luther’s criticisms with the Assertio, written with More's assistance. Pope Leo X rewarded the English king with the title 'Fidei defensor' ("Defender of the Faith") for his work combating Luther’s heresies.

More insisted upon giving his daughters the same classical education as his son, a highly unusual attitude at the time. His eldest daughter, Margaret, attracted much admiration for her erudition, especially her fluency in Greek and Latin. More told his daughter of his pride in her academic accomplishment in September 1522, after he showed the bishop a letter she had written:

Martin Luther then attacked Henry VIII in print, calling him a "pig, dolt, and liar". At the king's request, More composed a rebuttal: the Responsio ad Lutherum was published at the end of 1523. In the Responsio, More defended papal supremacy, the sacraments, and other Church traditions. More, though considered "a much steadier personality", described Luther as an "ape", a "drunkard", and a "lousy little friar" amongst other epithets. Writing under the pseudonym of Gulielmus Rosseus, More tells Luther that:

Confronting Luther confirmed More's theological conservatism. He thereafter avoided any hint of criticism of Church authority. In 1528, More published another religious polemic, A Dialogue Concerning Heresies, that asserted the Catholic Church was the one true church, established by Christ and the Apostles, and affirmed the validity of its authority, traditions and practices. In 1529, the circulation of Simon Fish’s Supplication for the Beggars prompted More to respond with The Supplication of Souls.

As the conflict over supremacy between the Papacy and the King reached its apogee, More continued to remain steadfast in supporting the supremacy of the Pope as Successor of Peter over that of the King of England. Parliament's reinstatement of the charge of praemunire in 1529 had made it a crime to support in public or office the claim of any authority outside the realm (such as the Papacy) to have a legal jurisdiction superior to the King's.

In 1530, More refused to sign a letter by the leading English churchmen and aristocrats asking Pope Clement VII to annul Henry's marriage to Catherine of Aragon, and also quarrelled with Henry VIII over the heresy laws. In 1531, a royal decree required the clergy to take an oath acknowledging the King as "Supreme Head" of the Church in England. The bishops at the Convocation of Canterbury in 1532 agreed to sign the Oath but only under threat of praemunire and only after these words were added: "as far as Christ law allows". This was considered to be the final Submission of the Clergy. Cardinal John Fisher and some other clergy refused to sign. Henry purged most clergy who supported the papal stance from senior positions in the church. More continued to refuse to sign the Oath of Supremacy and did not agree to support the annulment of Henry's marriage to Catherine. However, he did not openly reject the King's actions and kept his opinions private.

Jeremy Northam depicts More in the television series The Tudors as a peaceful man, as well as a devout Roman Catholic and loving family patriarch. He also shows More loathing Protestantism, burning both Martin Luther's books and English Protestants who have been convicted of heresy. The portrayal has unhistorical aspects, such as that More neither personally caused nor attended Simon Fish's execution (since Fish actually died of bubonic plague in 1531 before he could stand trial), although More's The Supplycatyon of Soulys, published in October 1529, addressed Fish's Supplication for the Beggars. Indeed, there is no evidence that More ever attended the execution of any heretic. The series also neglected to show More's avowed insistence that Richard Rich's testimony about More disputing the King's title as Supreme Head of the Church of England was perjured.

On 16 May 1532, More resigned from his role as Chancellor but remained in Henry's favour in spite of his refusal. His decision to resign was caused by the decision of the convocation of the English Church, which was under intense royal threat, on the day before.

In 1533, More refused to attend the coronation of Anne Boleyn as the Queen of England. Technically, this was not an act of treason, as More had written to Henry seemingly acknowledging Anne's queenship and expressing his Desire for the King's happiness and the new Queen's health. Despite this, his refusal to attend was widely interpreted as a snub against Anne, and Henry took action against him.

Regardless of the specific charges, the indictment related to violation of the Treasons Act 1534 declared it treason to speak against the King's Supremacy:

The execution took place on 6 July 1535. When he came to mount the steps to the scaffold, its frame seeming so weak that it might collapse, More is widely quoted as saying (to one of the officials): "I pray you, master Lieutenant, see me safe up and [for] my coming down, let me shift for my self"; while on the scaffold he declared that he died "the king's good servant, and God's first." After More had finished reciting the Miserere while kneeling, the executioner reportedly begged his pardon, then More rose up merrily, kissed him and gave him forgiveness.

Sir Thomas More is a play written circa 1592 in collaboration with Henry Chettle, Anthony Munday, william Shakespeare, and others. In it More is portrayed as a wise and honest statesman. The original manuscript has survived as a handwritten text that shows many revisions by its several authors, as well as the censorious influence of Edmund Tylney, Master of the Revels in the government of Queen Elizabeth I. The script has since been published and has had several productions.

Pope Leo XIII beatified Thomas More, John Fisher and 52 other English Martyrs on 29 December 1886. Pope Pius XI canonised More and Fisher on 19 May 1935, and More's feast day was established as 9 July. Since 1970 the General Roman Calendar has celebrated More with St John Fisher on 22 June (the date of Fisher's execution). On 31 October 2000 Pope John Paul II declared More "the heavenly Patron of Statesmen and Politicians". More is the patron of the German Catholic youth organisation Katholische Junge Gemeinde.

Many see More's communism or socialism as purely satirical. In 1888, while praising More's communism, Karl Kautsky pointed out that "perplexed" historians and economists often saw the name Utopia (which means "no place") as "a subtle hint by More that he himself regarded his communism as an impracticable dream".

The Crown confiscated More's home and estate along the Thames in Chelsea after his execution. Crosby Hall, which was part of More's London residence, was eventually relocated and reconstructed in Chelsea by conservation Architect Walter Godfrey in 1910. Rebuilt in the 1990s, the white stone building stands amid modern brick structures that attempt to recapture the style of More's former manor on the site. Crosby Hall is privately owned and closed to the public. The modern structures face the Thames and include an entry way that displays More's arms, heraldic beasts, and a Latin maxim. Apartment buildings and a park cover the former gardens and orchard; Roper's Garden is the park atop one of More's gardens, sunken as his was believed to be. No other remnants exist of the More estate.

More had no children from his second marriage, although he raised Alice's daughter from her previous marriage as his own. More also became the guardian of two young girls: Anne Cresacre would eventually marry his son, John More; and Margaret Giggs (later Clement) would be the only member of his family to witness his execution (she died on the 35th anniversary of that execution, and her daughter married More's nephew william Rastell). An affectionate father, More wrote letters to his children whenever he was away on legal or government Business, and encouraged them to write to him often.

Across a small park and Old Church Street from Crosby Hall is Chelsea Old Church, an Anglican church whose southern chapel More commissioned and in which he sang with the parish choir. Except for his chapel, the church was largely destroyed in the Second World War and rebuilt in 1958. The capitals on the medieval arch connecting the chapel to the main sanctuary display symbols associated with More and his office. On the southern wall of the sanctuary is the tomb and epitaph he erected for himself and his wives, detailing his ancestry and accomplishments in Latin, including his role as peacemaker between the Christian nations of Europe as well as a curiously altered portion about his curbing heresy. When More served Mass, he would leave by the door just to the left of it. He is not, however, buried here, nor is it entirely certain which of his family may be. It is open to the public at specific times. Outside the church, facing the River Thames, is a statue by L. Cubitt Bevis erected in 1969, commemorating More as "saint", "scholar", and "statesman"; the back displays his coat-of-arms. Nearby, on Upper Cheyne Row, the Roman Catholic Church of Our Most Holy Redeemer & St. Thomas More honours the martyr.

The 20th-century agnostic Playwright Robert Bolt portrayed Thomas More as the tragic hero of his 1960 play A Man for All Seasons. The title is drawn from what Robert Whittington in 1520 wrote of More:

Note: The reference "CW" is to the relevant volume of the Yale Edition of the Complete Works of St. Thomas More (New Haven and London 1963–1997)

In 1966, the play, A Man for All Seasons, was adapted into a film with the same title. It was directed by Fred Zinnemann and adapted for the screen by the Playwright. It stars Paul Scofield, a noted British actor, who said that the part of Sir Thomas More was "the most difficult part I played." The film won the Academy Award for Best Picture and Scofield won the Best Actor Oscar. In 1988 Charlton Heston starred in and directed a made-for-television film that restored the character of "the Common man" that had been cut from the 1966 film.

More is the focus of the Al Stewart song "A Man For All Seasons" from the 1978 album Time Passages, and of the Far song "Sir", featured on the limited editions and 2008 re-release of their 1994 album Quick. In addition, the song "So Says I" by indie rock outfit The Shins alludes to the socialist interpretation of More's Utopia.

In 1980, despite their opposing the English Reformation, More and Fisher were jointly added as martyrs of the reformation to the Church of England's calendar of "Saints and Heroes of the Christian Church", to be commemorated every 6 July (the date of More's execution) as "Thomas More, Scholar, and John Fisher, Bishop of Rochester, Reformation Martyrs, 1535".

Among other surviving relics is his hair shirt, presented for safe keeping by Margaret Clement. This was long in the custody of the community of Augustinian canonesses who until 1983 lived at the convent at Abbotskerswell Priory, Devon. Some sources, including one from 2004, claimed that the hair shirt was then at the Martyr's church on the Weld family's estate in Chideock, Dorset. The most recent reports indicate that it is now preserved at Buckfast Abbey, near Buckfastleigh in Devon.

In 2002, More was placed at number 37 in the BBC's poll of the 100 Greatest Britons.

In 2008, More was portrayed on stage in Hong Kong as an allegorical symbol of the pan-democracy camp resisting Chinese Communism in a translated and modified version of Robert Bolt's play A Man for All Seasons .

The Novelist Hilary Mantel's portrays More as an unsympathetic persecutor of Protestants, and an ally of the Habsburg empire, in her 2009 novel Wolf Hall, told from the perspective of a sympathetically portrayed Thomas Cromwell.

Having been praised "as a Communist hero by Karl Marx, Friedrich Engels, and Karl Kautsky" because of the Communist attitude to property in his Utopia, under Soviet Communism the name of Thomas More was in ninth position from the top of Moscow's Stele of Freedom (also known as the Obelisk of Revolutionary Thinkers), as one of the most influential thinkers "who promoted the liberation of humankind from oppression, arbitrariness, and exploitation." This monument was erected in 1918 in Aleksandrovsky Garden near the Kremlin at Lenin's suggestion. It was dismantled on 2 July 2013, during Vladimir Putin's third term as President of post-Communist Russia.

A portrait of More and his family was painted by Holbein, but it was lost in a fire in the 18th century. More's grandson commissioned a copy, of which two versions survive.