Ferdinand Joseph Lamothe was born into a Creole community in the Faubourg Marigny neighborhood of downtown New Orleans, Louisiana. His parents were Edward J. Lamothe and Louise Monette (written as Lemott and Monett on his baptismal certificate) but no birth certificate has been found to date. He took the name "Morton" by Anglicizing the name of his step-father, Mouton.

He was (along with Tony Jackson) one of the best regarded pianists in the Storyville District early in the 20th century. Tony Jackson was the main influence on his music; and according to Morton, Jackson was the only pianist better than him.

After leaving New Orleans, Morton traveled widely in North America, spending several years in California before moving to Chicago, Illinois in 1923, where he released the first of his commercial recordings, both as a piano soloist and with various jazz bands. In 1926 Morton succeeded in getting a contract to make recordings for the USA's largest and most prestigious company, Victor. This gave him a chance to bring a well rehearsed band to play his arrangements in Victor's Chicago recording studios.

These recordings by Jelly Roll Morton & His Red Hot Peppers are regarded as classics of 1920s jazz. The Red Hot Peppers featured such other New Orleans jazz luminaries as Kid Ory, Omer Simeon, Barney Bigard, Johnny Dodds, and Baby Dodds. Jelly Roll Morton & His Red Hot Peppers were one of the first acts booked on tours by MCA.

Morton moved to New York City in 1928, where he continued to record for Victor. His piano solos and trio recordings are well regarded, but his band recordings suffer in comparison with the Chicago sides where Morton could draw on many great New Orleans musicians for sidemen. In New York, Morton had trouble finding musicians who wanted to play his style of jazz. With the Great Depression and the near collapse of the phonograph record industry, Morton's recording contract was not renewed by Victor for 1931. Morton continued playing less prosperously in New York, briefly had a radio show in 1934, then was reduced to touring in the band of a traveling burlesque act.

He wound up in Washington D.C., where folklorist Alan Lomax first heard Morton playing solo piano. In May, 1938, Lomax began recording interviews with Morton for the Library of Congress. The sessions, originally intended as a short interview with musical examples for use by music researchers in the Library of Congress, soon expanded to record more than eight hours of Morton talking and playing piano. Despite the low fidelity of these non-commercial recordings, their musical and historical importance attracted jazz fans, and portions have repeatedly been issued commercially. These interviews helped assure Morton's place in jazz history. During the period when he was recording his interviews, Morton was seriously injured by knife wounds when a fight broke out at the Washington, D.C. dive he was playing in. His recovery from his wounds was incomplete, and thereafter he was often ill and easily became short of breath.

He then moved to Los Angeles, California with a series of manuscripts of new tunes and arrangements, planning to form a new band and restart his career. However he took seriously ill shortly after his arrival and died on July 10, 1941, after an eleven-day stay in Los Angeles County General Hospital.