Lockhart, the son of a Presbyterian minister descended from the landed gentry, studied at the universities of Glasgow and Oxford and began the practice of law in Edinburgh in 1816. He was too reserved for the law, however, and turned to writing.

Lockhart became one of the main contributors to the Tory-oriented Edinburgh Monthly Magazine (later Blackwood's Edinburgh Magazine) from the time of its founding in 1817. With others, he wrote the “Translation from an Ancient Chaldee Manuscript,” which lampooned Scottish celebrities in a parody of Old Testament style; this article made Blackwood's an immediate succès de scandale. Another article, “On the Cockney School of Poetry,” was the first of a series of attacks on the English poets John Keats and Percy Bysshe Shelley, as well as on Leigh Hunt, leader of the “school” by virtue of his friendship with Keats, and on William Hazlitt, the critic and essayist. The article was published under a collective pseudonym but was mainly written by Lockhart.

In 1818 Lockhart met Sir Walter Scott (Scott, Sir Walter, 1st Baronet), the “elder statesman” of European Romanticism. Lockhart married Scott's daughter Sophia in 1820, became, through his influence, editor (1825–53) of the Tory Quarterly Review, and inherited Scott's Abbotsford estate. Though attacked by contemporaries for exposing Scott's faults, Lockhart's Life is now regarded as an idealized portrait, depicting Scott's success in brilliant colour, indicating his foibles with subtle wit, and treating the follies of the Ballantynes, Scott's first publishers, with partisan disregard for truth.

During his long tenure at The Quarterly Review, Lockhart contributed much sound literary criticism, giving judicious praise to William Wordsworth, Samuel Taylor Coleridge, Shelley, and Lord Byron. Early in his editorship (1828) he produced a biography of Robert Burns that showed sympathetic insight into that Scottish poet's life. Other works include a “daring” novel about a clergyman's surrender to sexual temptation, Adam Blair (1822).