Désormière was born in Vichy in 1898. He studied at the Paris Conservatoire, where his professors included Philippe Gaubert, Xavier Leroux and Charles Koechlin, and Vincent d'Indy. In 1922 he won the Prix Blumenthal and in 1923 became part of the Ecole d’Arcueil.
Désormière’s early conducting experience was largely with the Ballets suédois and Sergei Diaghilev's Ballets Russes. He was conductor of the Ballets suédois's premiere of Relâche (1924), a film and music presentation by Francis Picabia and Erik Satie, with the film segment, Entr'acte, directed by René Clair. He then worked for the Diaghilev company from 1925 until the impresario's death, conducting the premieres of Barabau by Vittorio Rieti, The Prodigal Son and Le pas d'acier by Sergei Prokofiev, and La Chatte by Henri Sauguet.
Beginning in 1932 he became closely involved in music for films with Pathé-Nathan, composing music for La Règle du jeu, Le Mariage de Chiffon, and Le Voyageur de la Toussaint. He also conducted the orchestra in over 20 other films, such as Partie de campagne,Remorques, La Belle et la bête, and La Beauté du diable.
He conducted the first complete recording of Claude Debussy's opera Pelléas et Mélisande, the sessions taking place in the salle de l’ancien Conservatoire, Paris, from 24 April to 26 May 1941, during the Nazi occupation, with the 20-record set being issued in January 1942. He also recorded excerpts from Chabrier’s L'étoile with Opéra-Comique forces during the war. During the occupation of Paris he was a member of the Front National des Musiciens; after Milhaud was forced to leave France, Désormière saved his paintings and personal possessions as well as paying the apartment rent during the Occupation.
He also won considerable fame as an enthusiastic champion of 20th-century repertoire. At the other chronological extreme, Désormière edited and performed early music, reviving mostly forgotten compositions by the likes of François Couperin, Jean-Philippe Rameau, and Michel Richard Delalande. From 1937 he was a leading conductor for the Paris Opéra-Comique, conducting, in addition to the creations below and recordings above, Une éducation manquée, L'heure espagnole, Le médecin malgré lui, Don Quichotte and L’Enlèvement au Sérail. He became an associate director of the Paris Opéra from 1945 to 1946.
While driving in Rome during 1952, he suffered a massive paralytic stroke that ended all his musical activities. Aphasic for the rest of his life, he remained a recluse. He died in Paris in 1963.