Poulenc was largely self-taught. His first compositions—Rapsodie Nègre (1917), Trois Mouvements Perpétuels, for piano, and Sonata for Piano Duet (1918) and his settings of Guillaume Apollinaire's poem Le Bestiaire and Jean Cocteau's Cocardes (1919)—were witty pieces with streaks of impudent parody. Humour remained an important characteristic of his music, as in the Surrealistic comic opera Les Mamelles de Tirésias (1947; The Breasts of Tiresias), based on a farce by Apollinaire.

In 1920 the critic Henri Collet grouped Poulenc with five other young French composers, calling them “Les Six.” The others were Arthur Honegger, Darius Milhaud, Georges Auric, Germaine Tailleferre, and Louis Durey; although they reacted in the same way to the emotionalism of 19th-century Romantic music and the Impressionism of Claude Debussy, they were in fact united by friendship more than by aesthetic ideals. Poulenc studied with the composer and teacher Charles Koechlin from 1921 to 1924. His ballet Les Biches (English title The Houseparty) was produced by Sergey Diaghilev in 1924. He composed his song cycles Poèmes de Ronsard and Chansons gaillardes in 1924 and 1926. There followed more than 100 songs, chiefly on poems by Apollinaire (e.g., “Banalités,” 1940), and Paul Éluard (e.g., “Tel jour, telle nuit,” 1937).

In 1934 Poulenc appeared as piano accompanist to the baritone Pierre Bernac in the first of many recitals over several years, an experience that deepened his understanding of the song as an art form. His songs, which range from parody to tragedy, are admired for their lyricism and for their sensitive integration of vocal line and accompaniment. His Concert champêtre for harpsichord (or piano) and orchestra (1928) was written at the suggestion of harpsichordist Wanda Landowska. Like many of his keyboard works, it mingles the light, urbane character of 18th-century French keyboard music with 20th-century harmonies.

During the 1930s Poulenc wrote many religious works, including Litanies à la Vierge Noire de Rocomadour (1936), Mass in G Major (1937), and Stabat Mater (1951). He participated in the French resistance movement during World War II. Figure humaine (performed 1945), a cantata based on poems by Éluard, voiced the spirit of the resistance and was secretly printed during the Nazi occupation. His opera Les dialogues des Carmélites (1953–56, libretto by Georges Bernanos) is considered one of the finest operas of the 20th century. Other widely performed works by Poulenc were the Sextet for piano and wind quintet (1930–32), Organ Concerto (1938), and Oboe Sonata (1962).