Smollett was born at Dalquhurn, now part of Renton, in present-day West Dunbartonshire, Scotland. He was the fourth son of Archibald Smollett of Bonhill, a judge and land-owner who died about 1726, and Barbara Cunningham, who died about 1766. He was educated at the University of Glasgow, where he qualified as a surgeon; it has been asserted by some biographers that he then proceeded to the University of Edinburgh but left without earning a degree. His career in medicine came second to his literary ambitions; during 1739 he went to London to seek 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. During 1742 he served as a surgeon during the disastrous campaign to capture Cartagena. On his return, he established practice in Downing Street and married a wealthy Jamaican heiress, Anne "Nancy" Lascelles (1721–1791), during 1747. She was a daughter of William Lascelles. They had one child, a daughter Elizabeth, who died aged 15 years about 1762. He had a brother, Capt. James Smollet, and a sister, Jean Smollett, who married Alexander Telfair of Symington, Ayrshire. Jean succeeded to Bonhill after the death of her cousin-german, Mr. Commissary Smollett, and resumed her maiden name of Smollett during 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, his poetry was described as 'delicate, sweet and murmurs as a stream'. The Adventures of Roderick Random was modelled on Le Sage's Gil Blas, and was published during 1748. After that Smollett finally had his tragedy, The Regicide, published, though it was never performed. During 1750, Smollett was granted his MD degree in Aberdeen, and also travelled to France, where he obtained material for his second novel, The Adventures of Peregrine Pickle, another success. Having lived for a brief time in Bath, he returned to London and published The Adventures of Ferdinand Count Fathom during 1753. He was now recognised as a major author, whose novels were published by the well-known London bookseller Andrew Millar. Smollett became associated with the likes of David Garrick, Laurence Sterne, Oliver Goldsmith and Samuel Johnson, whom he famously nicknamed "that Great Cham of literature". During 1755 he published an English translation of Miguel de Cervantes's novel Don Quixote, which he revised during 1761. During 1756, he became editor of the magazine 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 brief 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 the publication Travels through France and Italy (1766). He also published The History and Adventures of an Atom (1769), which gave his opinion of British politics during the Seven Years' War in the guise of a tale from ancient Japan.
He also re-visited Scotland and this visit helped inspire his last novel, The Expedition of Humphry Clinker (1771), published during 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 in the old English cemetery in Livorno, Italy.
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 during 2002, with an explanatory plaque. After his death in Italy during 1771 his cousin Jane Smollett had the monument built in Renton during 1774. It comprises a tall Tuscan column topped by an urn. On the plinth is a Latin inscription written by Professor George Stuart of Edinburgh, John Ramsay of Ochtertyre and Dr Samuel Johnson. It is a category A listed building.
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 may well be true if it was the house of his sister.
Smollett is one of the sixteen Scottish writers and poets depicted on the lower section of the Scott Monument on Princes Street in Edinburgh. He appears on the far left side of the east face.
There is a street in Nice, Alpes Maritimes France named after him.
The Expedition of Humphry Clinker was made into a radio series, with three one-hour episodes, dramatised by Yvonne Antrobus, starring Stuart McLoughlin as Clinker and Nigel Anthony as Mathew Bramble.