Abandoning the idea of going on the stage which he had briefly entertained, Lawrence came to London in 1787, was kindly received by Sir Joshua Reynolds, and became a student at the Royal Academy. He began to exhibit almost immediately, and his reputation increased so rapidly that he became an associate of the Academy in 1791. The death of Sir Joshua in 1792 opened the way to further successes. Lawrence was at once appointed painter to the Dilettanti Society, and principal painter to King George III in lieu of Reynolds. In 1794 he was a Royal Academician, and he became the fashionable portrait painter of the age, his sitters including England's most notable people, and ultimately most of the crowned heads of Europe. Caroline of Brunswick was one of his favourite subjects, and is reputed to have been his lover for a time.

He was never married.

Financial problems plagued Lawrence. In 1796, Lord Seaforth, one of Lawrence's close patrons, gave him £1,000 (equivalent to about £77 thousand in present day terms) to relieve him from his financial difficulties. Lawrence painted several portraits for Lord Seaforth, including a full-length portrait of Seaforth's daughter, Mary.

In 1815 Lawrence was knighted; in 1818 he went to Aachen to paint the sovereigns and diplomats gathered there for the third congress, and visited Vienna and Rome, everywhere receiving flattering marks of distinction from princes, due as much to his courtly manners as to his merits as an artist. After eighteen months he returned to England, and on the very day of his arrival was chosen president of the Academy in place of Benjamin West, who had died a few days before. He held the office from 1820 to his death. On 28 February 1822 he was elected as a Fellow of the Royal Society "for his eminence in art".

Sir Thomas Lawrence had all the qualities of personal manner and artistic style necessary to make a fashionable painter, and among English portrait painters he takes a high place, though not as high as that given to him in his lifetime. His more ambitious works of history painting in the classical style, such as his once celebrated "Satan," are practically forgotten, as is the fate of most such efforts by British artists of the period, including Reynolds.

The best display of Lawrence's work is in the Waterloo Gallery of Windsor, a collection of much historical interest, along with his famous painting of the Duke of Wellington. "Master Charles William Lambton" also known as "The Red Boy" (1825), painted for Lord Durham at the price of 600 guineas, is regarded as one of his best portraits. There are works in most British museums, especially the National Gallery, London, and Tate Britain, and many in American museums, exported during the early 20th century craze there for English portraits. "Pinkie" in The Huntington is a good example. The Vatican Pinacoteca has a swagger portrait of himself presented by George IV as almost its only British work. The Life and Correspondence of Sir T. Lawrence, by DE Williams, appeared in 1831.