In 1932, when Carlisle was still in her teens, Fats Waller discovered her while she was a Cincinnati, Ohio performer. Her piano style was influenced by Waller's. She incorporated humor into her sets.
In the 1940s, Carlisle recorded as a leader with Bluebird Records.
Carlisle also saw success as a songwriter. Her 1941 song, "Walkin' by the River", made her the first black woman to have a composition on any United States' Billboard chart. She had her own radio show The Una Mae Carlisle Radio Show on WJZ-ABC. That made her "the first Black American to host a national radio show." Later in the 1940s, Carlisle hosted several television programs.