He was born in the manse of Cambusnethan House in Lanarkshire, where his father, Dr John Lockhart, transferred in 1796 to Glasgow, was minister.

His mother, who was the daughter of the Rev. John Gibson, of Edinburgh, was a woman of considerable intellectual gifts. He was sent to the Glasgow High School, where he showed himself clever rather than industrious. He fell into ill-health, and had to be removed from school before he was twelve; but on his recovery he was sent at this early age to Glasgow University, and displayed so much precocious learning, especially in Greek, that he was offered a Snell exhibition at Oxford. He was not fourteen when he entered Balliol College, Oxford, where he acquired a great store of knowledge outside the regular curriculum. He read French, Italian, German and Spanish, was interested in classical and British antiquities, and became versed in heraldic and genealogical lore.

In 1813 he took a first class in classics in the final schools. For two years after leaving Oxford he lived chiefly in Glasgow before settling to the study of Scots law in Edinburgh, where he was elected to the Faculty of Advocates in 1816. A tour on the continent in 1817, when he visited Goethe at Weimar, was made possible by the kindness of the publisher Blackwood, who advanced money for a promised translation of Schiegel's Lectures on the History of Literature, which was not published until 1838. Edinburgh was then the stronghold of the Whig party, whose organ was the Edinburgh Review, and it was not till 1817 that the Scottish Tories found a means of expression in Blackwood's Magazine. After a somewhat hum-drum opening, Blackwood suddenly electrified the Edinburgh world by an outburst of brilliant criticism. John Wilson (Christopher North) and Lockhart had joined its staff in 1817. Lockhart no doubt took his share in the caustic and aggressive articles which marked the early years of Blackwood; but his biographer, Mr Andrew Lang, brings evidence to show that he was not responsible for the virulent articles on Coleridge and on "The Cockney School of Poetry" - that is, on Leigh Hunt, Keats and their friends. He has been persistently accused of the later Blackwood article (August 1818) on Keats, but he showed at any rate a real appreciation of Coleridge and Wordsworth.

He contributed to Blackwood many spirited translations of Spanish ballads, which in 1823 were published separately. In 1818 the brilliant and handsome young man attracted the notice of Sir Walter Scott, and the acquaintance soon ripened into an intimacy which resulted in a marriage between Lockhart and Scott's eldest daughter Sophia, in April 1820. Five years of domestic happiness followed, with winters spent in Edinburgh and summers at a cottage at Chiefswood, near Abbotsford, where Lockhart's two eldest children, John Hugh and Charlotte, were born; a second son, Walter, was born later at Brighton.

In 1820 John Scott, the editor of the London Magazine, wrote a series of articles attacking the conduct of Blackwood's Magazine, and making Lockhart chiefly responsible for its extravagances. A correspondence followed, in which a meeting between Lockhart and John Scott was proposed, with Jonathan Henry Christie and Horace Smith as seconds. A series of delays and complicated negotiations resulted early in 1821 in a duel between Christie and John Scott, in which Scott was killed. This unhappy affair, which has been the subject of much misrepresentation, is fully discussed in Andrew Lang's book on Lockhart.

Between 1818 and 1825 Lockhart worked indefatigably. In 1819 Peter's Letters to his Kinsfolk appeared, and in 1822 he edited Peter Motteux's edition of Don Quixote, to which he prefixed a life of Cervantes. Four novels followed: Valerius in 1821, Some passages in the Life of Adam Blair, Minister of Gospel at Cross Meikle in 1822, Reginald Dalton in 1823 and Matthew Wald in 1824. But his strength did not lie in novel writing, although the vigorous quality of Adam Blair has been recognized by modern critics. In 1825 Lockhart accepted the editorship of the Quarterly Review, which had been in the hands of Sir John Taylor Coleridge since Gifford's resignation in 1824.

He had now established his literary position, and, as the next heir to his unmarried half-brother's property in Scotland, Milton Lockhart, he was sufficiently independent, though he had abandoned the legal profession. In London he had great social success, and was recognized as a brilliant editor. He contributed largely to the Quarterly Review himself, his biographical articles being especially admirable. He showed the old, railing spirit in an amusing but violent article in the Quarterly on Tennyson's Poems of 1833, in which he failed to discover the mark of genius.

He continued to write for Blackwood; he produced for Constable's Miscellany Volume XXIII in 1828 what remains the most charming of the biographies of Burns, his Life of Robert Burns. Because Lockhart was the only one of Burns's biographers to have been the author of a classic, his Burns has been treated with a respect and given a circulation which its merits, in spite of its graceful style do not justify. For it is misleading and dishonest. As Snyder puts it: 'The best that one can say of it today... is that it occasioned Carlyle's review. It is inexcusably inaccurate from beginning to end, at times demonstrably mendacious, and should never be trusted in any respect or detail.'.

He also undertook the superintendence of the series called "Murray's Family Library", which he opened in 1829 with a History of Napoleon.

But his chief work was the Life of Sir Walter Scott (7 vols, 1837...1838; 2nd ed., 10 vols., 1839). This edited a great number of Scott's letters. There were not wanting those in Scotland who taxed Lockhart with ungenerous exposure of his subject, but to most healthy minds the impression conveyed by the biography was, and is, quite the opposite. Carlyle did justice to many of its excellencies in a criticism contributed to the London and Westminster Review (1837). Lockhart's account of the transactions between Scott and the Ballantynes and Constable caused great outcry; and in the discussion that followed he showed unfortunate bitterness by his pamphlet, "The Ballantyne Humbug handled." The Life of Scott has been called, after Boswell's Johnson, the most admirable biography in the English language. The proceeds, which were considerable, Lockhart resigned for the benefit of Scott's creditors.

Lockhart's life was saddened by family bereavement, resulting in his own breakdown in health and spirits. His eldest boy (the suffering "Hugh Littlejohn" of Scott's Tales of a Grandfather) died in 1831; Scott himself in 1832; Mrs Lockhart in 1837; and the surviving son, Walter Lockhart, in 1852. Resigning the editorship of the Quarterly Review in 1853, he spent the next winter in Rome, but returned to England without recovering his health; and being taken to Abbotsford by his daughter Charlotte, who had become Mrs James Robert Hope-Scott, he died there on 25 November 1854. He was buried in Dryburgh Abbey, near Sir Walter Scott.

Robert Scott Lauder painted two portraits of Lockhart, one of him alone, and the other with Charlotte Scott.

Lockhart's Life (2 vols., London and New York, 1897) was written by Andrew Lang. A.W. Pollard's edition of the Life of Scott (1900), is the best.