Noble Sissle was exposed to music early through the church choir of his father, Reverend Andrew Sissle. He began singing professionally in 1908 with the Edward Thomas Male Quartet. In 1913 he received a full music scholarship to De Pauw University but remained there for only one semester before transferring to Butler University. While there, Sissle worked as a waiter at a large hotel and was persuaded by the owner to organize and conduct an orchestra to perform there. The hotel band became his first professional position as a band leader.

In 1916, Sissle settled in New York and began to work for James Reese Europe at his Clef Club and Tempo Club. Europe gave him the opportunity to work on some of the most important society dances and events. The same year he began to collaborate on popular songs with Eubie Blake, whom he had met the year before. The historic collaboration was halted when Sissle enlisted in the U.S. army, where he and James Reese Europe organized an all-black infantry band, the 39th Regimental Infantry Band. The 39th Infantry Band was scheduled to tour in 1919 when Europe was murdered by a disgruntled former member of the band. After this devastating blow, Sissle persuaded his backers to finance the team of Blake and Sissle as a duo; they adopted the name "The Dixie Duo".

The next year they met Flournoy Miller and Aubrey Lyles, who presented them with the idea for Shuffle Along. Shuffle Along opened in 1921 and ran for 504 performances, launching the careers of Josephine Baker, Florence Mills, Catherina Jarboro, Paul Robeson, and Adelaide Hall. Smash hits from the show included, I'm Just Wild About Harry, Bandana Days, and Love Will Find a Way. Originally planned for a black audience, the show ran two weeks at the Howard Theatre in Washington D.C. and at the Dunbar Theatre in Philadelphia, before opening at New York City's 63rd Street Music Hall on May 23, 1921. Shuffle Along marked the first time a love scene between two black performers was ever depicted on Broadway, and the first time black audiences were allowed to sit in formerly white-only sections of the theater. The show closed with a reported gross of eight million dollars.

After the success of Shuffle Along, Sissle and Blake collaborated on the musicals Chocolate Dandies in 1924 and Shuffle Along of 1933. Between 1924 and 1933, Sissle and Blake performed in London. Sissle also directed his own band at the Les Ambassadeurs in Paris in 1928. Although he found great success Paris, and London, he returned to the United States after the death of Aubrey Lyles, to work on Shuffle Along of 1933. In 1935 Sissle reorganized his orchestra and returned to Paris with Lena Horne as his singer. He continued to perform with his band in the United States and toured with the USO. He also started his own publishing company in the 1960s and became president of the Negro Actor's Guild, which he helped found.