She performed the role of Clara in the premiere production of George Gershwin's Porgy and Bess in 1935, and was also the first to record "Summertime" from that musical.

Mitchell was the mixed-race daughter of an African-American mother and a Jewish-German father from New York City's Lower East Side.

At the age of fourteen, she was discovered singing from the fire escape of her aunt's apartment by the composer Will Marion Cook and lyricist Paul Laurence Dunbar; they cast her for a role in their one-act musical comedy Clorindy: The Origin of the Cakewalk (1898).

Mitchell later performed with the "Black Patti's Troubadours", and in the operetta The Red Moon (1908) by Bob Cole and J. Rosamond Johnson.

In 1913, she appeared in the film Lime Kiln Field Day with Bert Williams, which was produced by Klaw and Erlanger, but they never finished or released it.

Lee de Forest made a short film, Songs of Yesteryear (1922), of Mitchell singing, using his DeForest Phonofilm sound-on-film process.