Noble Lee Sissle was born July 10, 1889, in Indianapolis, Indiana, the son of Rev. George A. Sissle, pastor of the city's Simpson M. E. Chapel, and Martha Angeline (nee Scott) Sissle, a school teacher and juvenile probation officer. The family moved to Cleveland, where he sang in church choirs and as a soloist with his high school glee club; as a teenager he won a discrimination suit against a Cleveland movie theater that had forced him into the balcony, one of the earliest NAACP-backed cases. He attended DePauw University in Greencastle, Indiana on scholarship, transferred to Butler University in Indianapolis, then left school for music. In 1914 he put together his first band for a residency at the Severin Hotel in Indianapolis. He moved to Baltimore in 1915 and worked in Bob Young's band, where the second pianist on some nights was Luckey Roberts and the regular pianist was Eubie Blake. Later that year Sissle led his own band at the Cocoanut Grove in Palm Beach, Florida.

In early 1916 he joined one of James Reese Europe's society orchestras in New York as a guitarist and vocalist, and persuaded Europe to hire Blake as well. When Europe organized a regimental band for the 15th Infantry Regiment (Colored) of the New York National Guard, later the 369th Infantry "Hell Fighters," Sissle enlisted with him in December 1916 and served as drum major and lead vocalist. The band played syncopated music rather than standard military repertoire and is credited with introducing jazz to France. Sissle had begun recording for Pathe in early 1917 and sang several vocals on the Pathe discs Europe's 369th band cut in early 1919 after it went civilian; the labels billed him as "Lieut. Noble Sissle." On May 9, 1919, Europe was stabbed to death in Boston by one of his own drummers, and Sissle, with Blake's help, took temporary charge of the band. He left the army as a second lieutenant with the 370th Infantry Regiment.

Sissle and Blake turned their songwriting partnership into a vaudeville act, the Dixie Duo, then built it out into a full production with the comedy team of Flournoy Miller and Aubrey Lyles, who wrote the book. Shuffle Along premiered at the 63rd Street Music Hall in 1921 and ran 504 performances, the first hit Broadway musical written by and about African Americans and the first all-Black show on Broadway in over a decade. Sissle wrote the lyrics to Blake's music, including "I'm Just Wild About Harry," which Harry Truman adopted as his 1948 campaign song, and "Love Will Find a Way." The cast and the touring companies carried Josephine Baker, Florence Mills, Adelaide Hall and Paul Robeson through early in their careers. The partners followed it with Elsie (1923) and The Chocolate Dandies (1924), the second a lavish production that lost money, and cut dozens of vocal-and-piano sides for Victor, OKeh and Edison between 1923 and 1927. They also made three Phonofilm sound shorts for Lee de Forest in 1923, among the earliest surviving film of Black musical performers.

The two played a 1926 residency at London's Kit Kat Club and returned to the United States that August, but Sissle went back to London alone in 1927 for a solo act accompanied by pianist Harry Revel, and the partnership lapsed. Cole Porter told him that Fred Waring's band was leaving Les Ambassadeurs in Paris and that the room wanted an American replacement; Sissle assembled a band for the summer 1928 residency there, and the French press began calling him "the Ace of Syncopation," a billing that turned up on his Parlophone record labels. He sailed for Paris again with his own band in May 1929 and worked Paris, Monte Carlo, Ostend and London before returning to New York in December 1930. The band he led through these years was a serious one. His HMV sessions at Hayes, Middlesex on September 10 and October 10, 1929 used clarinetist Buster Bailey, trumpeter Demas Dean and the violinist Juice Wilson; by the Columbia session in London on December 11, 1930, the trumpets were Arthur Briggs and Tommy Ladnier, with Rudy Jackson (recently out of Duke Ellington's band) and Frank "Big Boy" Goudie in the reeds and Gracie Fields guesting on a vocal. British Pathe filmed the band at Ciro's Club in London in 1931 playing "Little White Lies" and "Happy Feet," and a broadcast from New York's Park Central Hotel that year broke that hotel's color bar.

Sidney Bechet joined the band for its first American sessions after the return, cutting six Brunswick sides in New York on February 24 and April 21, 1931, alongside Ladnier and Briggs. Bechet stayed with Sissle on and off for most of the next seven years, and the association is the central fact of Sissle's jazz career: it kept Bechet working and recorded through the years when his own reputation had faded, and Sissle eventually built dates around him. The band appeared in the Vitaphone short That's the Spirit (1932) with Cora La Redd and cut four sides in Chicago on August 15, 1934 as Noble Sissle and His International Orchestra, including "Polka Dot Rag," which Bechet co-wrote with tenor saxophonist James Toliver and Sissle. A car crash in the summer of 1936 left Sissle injured and idled the band for a stretch. On March 11, 1936, in New York, the orchestra recorded six titles for Decca that included the first records Lena Horne ever made, at eighteen, "That's What Love Did to Me" and "I Take to You," cut while she was touring with the band as "Helena Horne"; the same session produced "You Can't Live in Harlem," with a half-chorus of Bechet's soprano. In April 1937 the full orchestra cut "Bandana Days," "I'm Just Wild About Harry" and "Dear Old Southland" for Variety, and two days later Sissle put Bechet in front of just his rhythm section as Noble Sissle's Swingsters for "Okey-Doke" and "Characteristic Blues." A last Swingsters date for Decca on February 10, 1938 produced "Viper Mad," "Blackstick," "Southern Sunset" and "Sweet Patootie," with Clarence Brereton on trumpet, Gil White on tenor and O'Neil Spencer on drums. Five of the six 1937-38 small-group sides were written or co-written by Bechet.

From 1938 Sissle led the house band at Billy Rose's Diamond Horseshoe in the basement of New York's Paramount Hotel, a residency he held for more than twelve years, interrupted by USO tours during World War II that included a trip to Europe and a traveling version of Shuffle Along. He was the first president of the Negro Actors Guild of America, formed in 1936 by Fredi Washington, W. C. Handy, Paul Robeson and Ethel Waters and operating from 1937. He broke publicly with Al Jolson over blackface in a signed 1938 Pittsburgh Courier piece. In 1950 he succeeded Bill "Bojangles" Robinson as honorary mayor of Harlem, and a Shuffle Along sequel reached Broadway in 1952. He played Eisenhower's 1953 inaugural, was signed as a disc jockey by New York station WMGM in January 1954 for a show built on Black recording artists, ran his own music publishing company, and operated a nightclub called Noble's. Repeated muggings led him to close the club and move to Florida. He reunited with Blake for recordings as late as 1969, and their last collaboration was a song honoring Martin Luther King Jr. He developed Alzheimer's disease in his final years and died in Tampa on December 17, 1975.

Sissle was a light, clearly enunciated tenor (Laird and Rust's discography describes him as a baritone, and the DAHR name file notes the disagreement) whose singing came out of the concert and glee-club tradition rather than the blues, which is exactly why the Sissle and Blake sides sound like a different music from what Bessie Smith or Louis Armstrong were cutting in the same years. His real contribution to jazz was made as an employer and an organizer. The bands he led between 1929 and 1938 were commercial dance orchestras with a string section, and jazz critics have been consistently hard on them: the Rust-derived Harlem Fuss discography calls the 1921 Sizzling Syncopators sides "mainly of historical interest, comprising very little jazz elements," and clarinetist and critic Eric Seddon judged Bechet "a bad fit in this sort of music" and mostly wasted in the section. But Sissle hired and kept working Bechet, Tommy Ladnier, Buster Bailey, Arthur Briggs, Rudy Jackson, Wendell Culley, Clarence Brereton and pianist Harry Brooks, and he gave Lena Horne her first job and her first records. By 1937 he had drawn the right conclusion from Benny Goodman's small groups and put Bechet out front on his own, producing the Swingsters sides that are the strongest jazz to carry Sissle's name. As a lyricist his reach was much wider than his own bandstand: "I'm Just Wild About Harry" and "Love Will Find a Way" entered the standard repertoire, and "Yeah Man!," with a Sissle lyric, became a swing-era feature for Fletcher Henderson's orchestra in 1933.