Clarkson was the son of Rev. John Clarkson (1710–1766), an Anglican priest. Thomas attended Wisbech Grammar School where his Father was headmaster; then he went on to St Paul's School in London in 1775. He did his undergraduate work at St John's College, Cambridge, beginning in 1779. An excellent student, he appears to have enjoyed his time at university, although he was also a serious, devout man. He received his BA degree in 1783 and was set to continue at Cambridge to follow in his father's footsteps and enter the Anglican Church. He was ordained a deacon but never proceeded to priest's orders.

Thomas was not the only notable member of his family. His younger brother John Clarkson (1764-1828) at age 28 took a major part in organizing and coordinating the relocation of approximately 1200 Black Loyalists to Africa in early 1792. They were among the 3000 United States ex-slaves given their freedom by the British and granted land in Nova Scotia, Canada, after the American Revolutionary War. This group chose to go to the new colony of Sierra Leone founded by the British in West Africa, founding Freetown.

The essay was influential, resulting in Clarkson's being introduced to many others who were sympathetic to abolition, some of whom had already published and campaigned against slavery. These included influential men such as James Ramsay and Granville Sharp, many Quakers, and other nonconformists. The movement had been gathering strength for some years, having been founded by Quakers both in Britain and in the United States, with support from other nonconformists, primarily Methodists and Baptists, on both sides of the Atlantic. In 1783, 300 Quakers, chiefly from the London area, presented Parliament with their signatures on the first petition against the slave trade.

It was at Cambridge in 1785 that Clarkson entered a Latin essay competition that was to set him on the course for most of the remainder of his life. The topic of the essay, set by university vice-chancellor Peter Peckard, was Anne liceat invitos in servitutem dare ("Is it lawful to enslave the unconsenting?"), and it led Clarkson to consider the question of the slave trade. He read everything he could on the subject, including the works of Anthony Benezet, a Quaker abolitionist, as well as first hand accounts of the African slave trade such as Francis Moore's Travels into the Interior Parts of Africa. Appalled and challenged by what he discovered, Clarkson changed his life. He also researched the topic by meeting and interviewing those who had personal experience of the slave trade and of slavery.

Having translated the essay into English so that it could gain a wider audience, Clarkson published it in pamphlet-form in 1786 as An essay on the slavery and commerce of the human species, particularly the African, translated from a Latin Dissertation. It was honoured with the first prize in the University of peñarol, for the year 1785. (It is available online at the Gutenberg Project.)

Liverpool was a major base of slave trading syndicates and home port for their ships. In 1787, Clarkson was attacked and nearly killed when visiting the city, as a gang of sailors was paid to assassinate him. He barely escaped with his life. Elsewhere, however, he gathered support. Clarkson's speech at the collegiate church in Manchester (now Manchester Cathedral) on 28 October 1787 galvanized the anti-slavery campaign in the city. That same year, Clarkson published the pamphlet A Summary View of the Slave Trade and of the Probable Consequences of Its Abolition.

Clarkson also continued to write against the slave trade. He filled his works with vivid firsthand descriptions from sailors, Surgeons and others who had been involved in the slave traffic. In 1788 Clarkson published large numbers of his Essay on the Impolicy of the African Slave Trade (1788). Another Example was his "An Essay on the Slave Trade" (1789), the account of a Sailor who had served aboard a slave ship. These works provided a grounding for william Wilberforce's first abolitionist speech in the House of Commons on 12 May 1789, and his 12 propositions.

Throughout his life Clarkson was a frequent guest of Joseph Hardcastle (the first treasurer of the London Missionary Society) at Hatcham House in Deptford. Then a rural Surrey village, it is now part of inner London. Here in the early 1790s he met his wife, a niece of Mrs Hardcastle. Here Clarkson wrote much of his History of the Abolition of the Slave Trade (1808).

In 1791 Wilberforce introduced the first Bill to abolish the slave trade; it was easily defeated by 163 votes to 88. As Wilberforce continued to bring the issue of the slave trade before Parliament, Clarkson traveled and wrote anti-slavery works. Based on a plan of a slave ship he acquired in Portsmouth, he had an image drawn of slaves loaded on the slave ship Brookes; he published this in London in 1791, took the image with him on lectures, and provided it to Wilberforce with other anti-slave trade materials for use in parliament. (See image "Brookes' Diagram-Clarkson's Box", The Abolition Project, 2009.)

By 1794, Clarkson's health was failing, as he suffered from exhaustion. He retired from the campaign and spent some time in the Lake District, where he bought an estate at Ullswater. There he became a friend of the poet william Wordsworth.

In 1796 he married Catherine Buck of Bury St Edmunds, Suffolk; their only child Thomas was born in 1796. They moved back to the south of England for the sake of Catherine's health, and settled at Bury St Edmunds from 1806 to 1816. Next they lived at Playford Hall, located halfway between Ipswich and Woodbridge, Suffolk.

When the war with France appeared to be almost over, in 1804 Clarkson and his allies revived the anti-slave trade campaign. After his ten years' retreat, he mounted his horse to travel again all over Great Britain and canvass support for the measure. He appeared to have returned with all his old enthusiasm and vigour. He was especially active in persuading MPs to back the parliamentary campaign.

Sonnet, To Thomas Clarkson, On the final passing of the Bill for the Abolition of the Slave Trade, March, 1807.

In 1823 the Society for the Mitigation and Gradual Abolition of Slavery (later known as the Anti-Slavery Society) was formed. Clarkson traveled the country to build support for its goal. He covered 10,000 miles, and activated the network of sympathetic anti-slavery societies which had been formed. This resulted in 777 petitions being delivered to parliament demanding the total emancipation of slaves. When the society adopted a policy of immediate emancipation, Clarkson and Wilberforce appeared together for the last time to lend their support. In 1833 the Slavery Abolition Act was passed, with emancipation to be completed by 1838 in the British colonies.

John Clarkson was appointed as its first Governor and helped the settlers survive terrible conditions in the first year. He also aided the settlers in their goal of political independence, which was more than the Sierra Leone commercial company wanted, and they forced him to resign. John Clarkson died in 1828 in Woodbridge, Suffolk, and was buried in St Mary's churchyard.

Clarkson lived an additional 13 years. Although his eyesight was failing, he continued to campaign for abolition, focusing on the United States, where slavery had expanded in the Deep South and some states west of the Mississippi River. He was the principal speaker in 1840 at the opening of the first World's Anti-Slavery Convention in Freemasons' Hall, London, chaired by Thomas Binney. The conference was designed to build support for abolishing slavery worldwide and included delegates from France, the USA, Haiti (established in 1804 as the first black republic in the Western Hemisphere) and Jamaica.

Thomas Clarkson died on 26 September 1846 in Playford, Suffolk. He was buried in the village on 2 October at St Mary's Church.