Reputed for his arrogance and self-promotion as often as recognized in his day for his musical talents, Morton claimed to have invented jazz outright in 1902 — much to the derision of later musicians and critics. The jazz historian, musician, and composer Gunther Schuller says of Morton's "hyperbolic assertions" that there is "no proof to the contrary" and that Morton's "considerable accomplishments in themselves provide reasonable substantiation". However, the scholar Katy Martin has argued that Morton's bragging was exaggerated by Alan Lomax in the book Mister Jelly Roll, and this portrayal has influenced public opinion and scholarship on Morton since.

Morton was born into a Creole of Color family in the Faubourg Marigny neighborhood of downtown New Orleans, Louisiana. Sources differ as to his birth date: a baptismal certificate issued in 1894 lists his date of birth as October 20, 1890; Morton and his half-sisters claimed he was born on September 20, 1885. His World War I draft registration card showed September 13, 1884, but his California death certificate listed his birth as September 20, 1889. He was born to F. P. Lamothe and Louise Monette (written as Lemott and Monett on his baptismal certificate). Eulaley Haco (Eulalie Hécaud) was the godparent. Hécaud helped choose his christening name of Ferdinand. His parents lived in a common-law marriage and were not legally married. No birth certificate has been found to date.

Ferdinand started playing music as a child, showing early talent. After his parents separated, his mother married a man named Mouton. Ferdinand took his stepfather's name and anglicized it as "Morton."

At the age of fourteen, Morton began working as a piano player in a brothel (or as it was referred to then, a sporting house.) While working there, he was living with his religious, church-going great-grandmother; he had her convinced that he worked as a night watchman in a barrel factory.

In that atmosphere, he often sang smutty lyrics; he took the nickname "Jelly Roll", which was black slang for female genitalia.

After Morton's grandmother found out that he was playing jazz in a local brothel, she kicked him out of her house. He said:

Tony Jackson, also a pianist at brothels and an accomplished guitar player, was a major influence on Morton's music. Jelly Roll said that Jackson was the only pianist better than he was.

Around 1904, Morton also started touring in the American South, working with minstrel shows, gambling and composing. His works "Jelly Roll Blues", "New Orleans Blues", "Frog-I-More Rag", "Animule Dance", and "King Porter Stomp" were composed during this period. He got to Chicago in 1910 and New York City in 1911, where future stride greats James P. Johnson and Willie "The Lion" Smith caught his act, years before the blues were widely played in the North.

In 1912–1914, Morton toured with his girlfriend Rosa Brown as a vaudeville act before settling in Chicago for three years. By 1914, he had started writing down his compositions. In 1915 his "Jelly Roll Blues" was arguably the first jazz composition ever published, recording as sheet music the New Orleans traditions that had been jealously guarded by the musicians. In 1917, he followed bandleader William Manuel Johnson and Johnson's sister Anita Gonzalez to California, where Morton's tango "The Crave" made a sensation in Hollywood.

Morton was invited to play a new Vancouver nightclub called The Patricia, on East Hastings Street. The jazz historian Mark Miller described his arrival as "an extended period of itinerancy as a pianist, vaudeville performer, gambler, hustler, and, as legend would have it, pimp".

Morton returned to Chicago in 1923 to claim authorship of his recently published rag, "The Wolverines", which had become a hit as "Wolverine Blues" in the Windy City. He released the first of his commercial recordings, first as piano rolls, then on record, both as a piano soloist and with various jazz bands.

In 1926, Morton succeeded in getting a contract to record for the largest and most prestigious company in the United States, 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, George Mitchell, Johnny St. Cyr, Barney Bigard, Johnny Dodds, Baby Dodds, and Andrew Hilaire. Jelly Roll Morton & His Red Hot Peppers were one of the first acts booked on tours by MCA.

In November 1928, Morton at the age of 38 married the showgirl Mabel Bertrand in Gary, Indiana.

They moved that year to New York City, where Morton 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. Although he recorded with the noted musicians clarinetists Omer Simeon, George Baquet, Albert Nicholas, Wilton Crawley, Barney Bigard, Lorenzo Tio and Artie Shaw, trumpeters Bubber Miley, Johnny Dunn and Henry "Red" Allen, saxophonists Sidney Bechet, Paul Barnes and Bud Freeman, bassist Pops Foster, and drummers Paul Barbarin, Cozy Cole and Zutty Singleton, Morton generally had trouble finding musicians who wanted to play his style of jazz. His New York sessions failed to produce a hit.

With the Great Depression and the near collapse of the record industry, Victor did not renew Morton's recording contract for 1931. Morton continued playing in New York, but struggled financially. He briefly had a radio show in 1934, then took on touring in the band of a traveling burlesque act for some steady income. His compositions were recorded by the musicians Fletcher Henderson, Benny Goodman and others, but he received no royalties from these recordings.

In 1935, Morton moved to Washington, D.C., to become the manager/piano player of a bar called, at various times, the "Music Box", "Blue Moon Inn", and "Jungle Inn" in the African-American neighborhood of Shaw. (The building that hosted the nightclub stands at 1211 U Street NW.) Morton was also the master of ceremonies, bouncer, and bartender of the club. He lived in Washington for a few years; the club owner allowed all her friends free admission and drinks, which prevented Morton from making the business a success.

In 1938 Morton was stabbed by a friend of the owner and suffered wounds to the head and chest. After this incident his wife Mabel demanded that they leave Washington.

During Morton's brief residency at the Music Box, the folklorist Alan Lomax heard the pianist playing in the bar. In May 1938, Lomax invited Morton to record music and interviews 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. Lomax also conducted longer interviews during which he took notes but did not record. Despite the low fidelity of these non-commercial recordings, their musical and historical importance have attracted numerous jazz fans, and they have helped to ensure Morton's place in jazz history.

Lomax was very interested in Morton's Storyville days and the ribald songs of the time. Although reluctant to recount and record these, Morton eventually obliged Lomax. Because of the suggestive nature of the songs, some of the Library of Congress recordings were not released until 2005.

In his interviews, Morton claimed to have been born in 1885. He was aware that if he had been born in 1890, he would have been slightly too young to make a good case as the inventor of jazz. He said in the interview that Buddy Bolden played ragtime but not jazz; this is not accepted by the consensus of Bolden's other New Orleans contemporaries. The contradictions may stem from different definitions for the terms ragtime and jazz. These interviews, released in different forms over the years, were released on an eight-CD boxed set in 2005, The Complete Library of Congress Recordings. This collection won two Grammy Awards. The same year, Morton was honored with the Grammy Lifetime Achievement Award.

When Morton was stabbed and wounded, a nearby whites-only hospital refused to treat him, as the city had racially segregated facilities. He was transported to a black hospital further away. When he was in the hospital, the doctors left ice on his wounds for several hours before attending to his eventually fatal injury. His recovery from his wounds was incomplete, and thereafter he was often ill and easily became short of breath. Morton made a new series of commercial recordings in New York, several recounting tunes from his early years that he discussed in his Library of Congress interviews.

Worsening asthma sent him to a New York hospital for three months at one point. He continued to suffer from respiratory problems when visiting Los Angeles with a series of manuscripts of new tunes and arrangements, planning to form a new band and restart his career. Morton died on July 10, 1941 after an eleven-day stay in Los Angeles County General Hospital.

According to the jazz historian David Gelly in 2000, Morton's arrogance and "bumptious" persona alienated so many musicians over the years that no colleagues or admirers attended his funeral. But, a contemporary news account of the funeral in the August 1, 1941 issue of Downbeat says that fellow musicians Kid Ory, Mutt Carey, Fred Washington and Ed Garland were among his pall bearers. The story notes the absence of Duke Ellington and Jimmie Lunceford, both of whom were appearing in Los Angeles at the time. (The article is reproduced in Alan Lomax's biography of Morton, Mister Jelly Roll, University of California Press, 1950.) Morton is buried in Calvary Cemetery, 4201 Whittier Blvd, Los Angeles, California, Section N, Lot 347, grave #4,in the north west quadrant of the cemetery.

Morton's piano style was formed from early secondary ragtime and "shout", which also evolved separately into the New York school of stride piano. Morton's playing was also close to barrelhouse, which produced boogie woogie.

Morton often played the melody of a tune with his right thumb, while sounding a harmony above these notes with other fingers of the right hand. This added a rustic or "out-of-tune" sound (due to the playing of a diminished 5th above the melody). This may still be recognized as belonging to New Orleans. Morton also walked in major and minor sixths in the bass, instead of tenths or octaves. He played basic swing rhythms in both the left and right hand.

Some of Morton's songs (listed alphabetically):

Several of Morton's compositions were musical tributes to himself, including "Winin' Boy", "The Jelly Roll Blues", subtitled "The Original Jelly-Roll"; and "Mr. Jelly Lord". In the Big Band era, his "King Porter Stomp", which Morton had written decades earlier, was a big hit for Fletcher Henderson and Benny Goodman; it became a standard covered by most other swing bands of that time. Morton claimed to have written some tunes that were copyrighted by others, including "Alabama Bound" and "Tiger Rag". "Sweet Peter," which Morton recorded in 1926, appears to be the source for the melody of the hit song "All Of Me," ostensibly written by Gerald Marks and Seymour Simons in 1931.

His musical influence continues in the work of Dick Hyman and Reginald Robinson.