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, which took 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 give his view of English 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, on which there is a Latin inscription composed by Dr. Johnson. The area around the monument was improved in 2002, with an explanatory plaque.