Most of the music for "Once Upon A Time in America" was composed by 1976.  This enabled it to be played on set in a simple form during shooting.  As with all the films that Leone directed from the Dollars trilogy onwards, Leone turned to Ennio Morricone to provide the original music.  Morricone has written scores for over 400 feature films, including The Battle of Algiers, Novecento, Days of Heaven, The Mission, The Untouchables, Cinema Paradiso, State of Grace, and Malena.

Besides the original music, the movie also uses several pieces of 'found music', including:

'God Bless America' (written by Irving Berlin, performed by Kate Smith - 1943) - Plays over the opening credits from a radio in Eve's bedroom.

'Yesterday' (written by John Lennon and Paul McCartney - 1965).  An instrumental version of this piece plays when Noodles' first returns to New York in 1968, examining himself in a train station mirror.  A version of the song also plays briefly during the dialogue scene between Noodles and "Bailey" towards the end of the film.

'Amapola' (written by Joseph M. Le Calle - 1923).  Actually originally an opera piece, several instrumental versions of this song were played during the film; a jazzy version which played on the gramophone danced to by young Deborah in 1922; a similar version played by Fat Moe's jazz band in the speakeasy in 1932; and a string version, during Noodles' date with Deborah. Both versions are available on the soundtrack.

'The Thieving Magpie' (Overture) (Gioacchino Rossini - 1817).  Used during the baby-switching scene in the hospital.

'Summertime' (George Gershwin - 1935).  Played by a jazz band during the beach scene after the beachgoers receive word of Prohibition's repeal.

'Night and Day' (written and sung by Cole Porter - 1932).  Plays during Secretary Bailey's party in 1968.

'Amapola' is the only piece of 'found music' to be included on the soundtrack album.