Morton was born in a New Orleans Creole community, and by the age of 14, was playing piano in the city's Storyville District brothels. In 1904, Morton began touring with minstrel shows through the South and composing his own tunes including "Jelly Roll Blues," which is often referred to as the first jazz composition to ever be published. In 1926, Morton signed with Chicago's Victor Records and released several albums with his band The Red Hot Peppers.

In 1935, Morton moved to Washington DC where he met folklorist Alan Lomax. Lomax recorded a series of interviews and performances with Morton for the Library of Congress. Many of these recordings weren't released until the latter part of the 20th century because many of Morton's songs from his days in Storyville's brothels are filled with sexual references. Lomax's recordings of Morton were released as an eight-CD box set in 2005 and were subsequently awarded two Grammys.

Morton died in a Los Angeles county hospital in 1941.