He was born in Sainte-Anne, Guadeloupe, out of wedlock, to Marie-Françoise Dupepaye, a free person of color, and Pierre Guillon, a colonial Royal Notary.

In 1774, after displaying an early aptitude for art, his father took him to France, where he was placed with the painter Jean-Baptiste Descamps, at the new free drawing school in Rouen.

Two years later, he entered again and, while he did not win, he succeeded in receiving support to travel to Rome, where he further developed his Neoclassical style.

The following year, he accompanied the newly appointed Ambassador, Lucien Bonaparte, to Spain, where he helped him build an art collection.

He created Erminia and the Shepherds (Dallas Museum of Art), a love story during the Renaissance and the Middle Ages.

[4] Lethière had finally arrived at the Académie de France in Rome, though contrary to his expectations, the campus had moved from the Palazzo Mancini to the Villa Medici, where conditions seemed desperate.

The latter were the lyrical Homer Singing His Iliad at the Gates of Athens (1814, Nottingham City Museums and Galleries), and the monumental version of Brutus Condemning his Sons to Death (1811, Musée du Louvre), which were both showcased in London from 1816 to 1819.

As a head of a studio, a director, and a professor, Lethière dedicated a lot of his time to mentoring the future generation.

His numerous well-known students included Horace Lecoq de Boisbaudran, Jean-Louis Gintrac, François Bouchot, Louis Boulanger, Jean-Auguste-Dominique Ingres, Eugène Devéria, Louis Joseph César Ducornet, Isidore Pils, Théodore Rousseau, Kanuty Rusiecki, Octave Tassaert, and his stepdaughter, Eugénie.