Thomson studied at Harvard University and later in Paris with Nadia Boulanger (Boulanger, Nadia), a noted teacher of musical composition. There he was influenced by early 20th-century French composers, especially the group known as Les Six (Six, Les), whose most prominent members were Darius Milhaud, Arthur Honegger, and Francis Poulenc. Thomson wrote in a variety of styles, including Gregorian chant, variations on Baptist hymns, and neoclassicism, often combining traditional forms with contemporary techniques, marked by careful craftsmanship. The greatest influence on him was that of Erik Satie (Satie, Erik), and it found expression in clarity, simplicity, and humour.

His operas are among his best-known works; Four Saints in Three Acts (1928) and The Mother of Us All (1947), the latter based on the life of Susan B. Anthony (Anthony, Susan B.), boast libretti by Thomson's close friend Gertrude Stein (Stein, Gertrude), an avant-garde American writer. A later opera was Lord Byron (1968), which combined and unified Thomson's various compositional styles. His instrumental music includes two symphonies, several symphonic poems, and concerti for cello and flute (composed 1950 and 1954, respectively).

Thomson composed songs, choral works, chamber music, piano pieces, and film music, including the scores for Pare Lorentz's (Lorentz, Pare) pioneering documentaries The River (1936) and The Plow that Broke the Plains (1937) and for Robert Flaherty (Flaherty, Robert)'s Louisiana Story (the film score of which won a Pulitzer Prize for music in 1949). He was music critic for the New York Herald Tribune (1940–54) and published several collections of penetrating, perceptive critical articles. His autobiography, Virgil Thomson, was published in 1966. Among his other books are Music Revisited, 1940–54 (1967), American Music Since 1910 (1971), and Selected Letters of Virgil Thomson (1988).