Smollett was born at Dalquhurn, now part of Renton, in present day West Dunbartonshire, Scotland. He was the son of a judge and land owner, and was educated at the University of Glasgow, qualifying as a surgeon. His career in medicine came second to his literary ambitions, and in 1739 he went to London to seek his fortune as a dramatist. Unsuccessful, he obtained a commission as a naval surgeon on HMS Chichester and travelled to Jamaica, where he settled down for several years. In 1742 he served as a surgeon during the disastrous campaign to capture Cartagena. On his return, he set up practice in Downing Street and married a wealthy Jamaican heiress, Anne Lascelles, in 1747. They had a daughter Elizabeth (only daughter) who died aged 15 years about 1762. He was the fourth son of Archibald Smollett of Bonhill, who died about 1726 and Barbara Cunningham who died about 1766. He had a brother, Capt. James Smollet and a sister Jean Smollett who married Alexander Telfair of Symington, Lanarkshire. Jean succeeded to Bonhill after the death of her cousin - german, Mr. Commissary Smollett and she resumed her maiden name of Smollett in 1780. They lived in St. John Street off Canongate, Edinburgh and had a son who was in the Military.

His first published work was a poem about the Battle of Culloden entitled "The Tears of Scotland", but it was The Adventures of Roderick Random which made his name. It was modelled on Le Sage's Gil Blas, and was published in 1748. Smollett followed it up by finally getting his tragedy, The Regicide, published, though it was never performed. In 1750, Smollett took his MD degree in Aberdeen, and also travelled to France, where he obtained material for his second novel, The Adventures of Peregrine Pickle, another big success. Having lived for a short time in Bath, he returned to London and published The Adventures of Ferdinand Count Fathom in 1753. He was now recognised as a leading literary figure, and associated with the likes of David Garrick, Laurence Sterne, Oliver Goldsmith and Samuel Johnson, whom he famously nicknamed "that Great Cham of literature". In 1755 he published a translation of Miguel de Cervantes's Don Quixote, which he revised in 1761. In 1756, he became editor of The Critical Review.

Smollett then began what he regarded as his major work, A Complete History of England, from 1757 to 1765. During this period he served a short prison sentence for libel, and produced another novel, The Life and Adventures of Sir Launcelot Greaves (1760).

Having suffered the loss of a daughter, he went abroad with his wife, and the result was Travels through France and Italy (1766). He also wrote The History and Adventures of an Atom (1769), which gave his view of British politics during the Seven Years' War under the guise of a tale from ancient Japan.

He also visited Scotland, and this visit helped inspire his last novel, The Expedition of Humphry Clinker (1771), published in the year of his death. He had for some time been ailing from an intestinal disorder, and had sought a cure at Bath and eventually retired to Italy, where he is buried at Leghorn (Livorno).

There is a monument to his memory beside Renton Primary School, Dunbartonshire, Scotland, on which there is a Latin inscription composed by Dr. Johnson. The area around the monument was improved in 2002, with an explanatory plaque. There is also a plaque to his temporary residence in Edinburgh just off the Royal Mile at the head of St John's Street. This states that he resided here in the house of his sister, Mrs. Telfer, for the summer of 1766. A second plaque (dating the building at 1758, making it relatively new at that time) states that he "stayed here occasionally" implying more than one visit, which way well be true if it was the house of his sister.