[2][3][4][5] The soundtrack features leitmotifs that relate to each of the main characters of the film (each with their own theme music), as well as to the spirit of the American West.

[6] The theme music for Jill McBain, Claudia Cardinale's character, has wordless vocals by Italian singer Edda Dell'Orso.

In 2020, in a retrospective on CineAction, Mark Lager wrote that "Morricone’s music in Once Upon a Time in the West and The Great Silence is magnificent in its melodic splendor and its revolutionary textures.

Claude Challe in his album Sun played a remix of "Man with a Harmonica" in CD 2 Lovely Sunset (released in 2001).

The German punk band Die Toten Hosen covered "Man with a Harmonica" under the title "Spiel mir das Lied vom Tod" on their 1984 album Unter falscher Flagge.