The son of a goldsmith, he was trained to follow his father's trade but had a passion for the theatre. He frequented the Comédie-Française and in 1748 began organizing amateur productions in which he starred. Voltaire witnessed one of his performances and, though impressed, nonetheless tried to discourage his stage career. When Lekain could not be dissuaded, Voltaire decided to coach him and to help him financially; Lekain made his debut at the Comédie-Française in 1754 as Titus in Voltaire's tragedy Brutus.

Though contemporaries described Lekain as small, ugly, and harsh-voiced, he overcame these disadvantages on the stage and became enormously popular with the public. He scored his greatest successes in plays by Voltaire, notably as Genghis Khan in L'Orphelin de la Chine and in the title role of Tancrède. In 1759 he drew up plans for a royal school of dramatic art. He strove to reform theatrical costume, discarding, for instance, the traditional heroic paraphernalia when playing Oreste in Racine's Andromaque and adopting a pseudo-Grecian costume instead. As a disciple of Voltaire, he campaigned successfully for more realistic scenery and for abolishing the contemporary custom of allowing privileged spectators to sit on the stage. His Mémoires were published in 1801.