Wiley was born in Fort Gibson, Oklahoma. At fifteen, she left home to pursue a singing career, singing on New York City radio stations. Her career was interrupted by a fall while horseback riding. She suffered temporary blindness but recovered. At the age of 19 she was a member of the Leo Reisman Orchestra, with whom in 1931 she recorded three songs: "Take It from Me", "Time On My Hands", and her composition "Got the South in My Soul".
Wiley began her radio career at KVOO in Tulsa, Oklahoma. She sang on the Mrs. Eleanor Roosevelt program on NBC in 1932, and was featured on Victor Young's radio show in 1933. From June 10, 1936, until September 2, 1936, she had her own show, Lee Wiley, on CBS.
In 1939, Wiley recorded eight Gershwin songs on 78s with a small group for Liberty Music Shop Records. The set sold well and was followed by 78s dedicated to the music of Cole Porter (1940) and Richard Rodgers & Lorenz Hart (1940 and 1954), Harold Arlen (1943), and 10" LPs dedicated to the music of Vincent Youmans and Irving Berlin (1951).
She sang with Paul Whiteman and later, the Casa Loma Orchestra. A collaboration with composer Victor Young resulted in several songs for which Wiley wrote the lyrics, including "Got the South in My Soul" and "Anytime, Anyday, Anywhere."
On October 11, 1963, Bob Hope Theater on NBC-TV presented "Something About Lee Wiley". Piper Laurie portrayed Wiley in the episode, which was produced by Revue Studios. Wiley's singing voice was provided by Joy Bryan.