He number 1 attracted attention singing by using Teddy Weatherford's band in Calcutta, India, which made regular radio broadcasts over a U. S. Armed Forces Radio Service in the period of World War II. Witherspoon processed his number one records with Jay McShann's band in 1945. Inside 1949, recording under his have title sustaining a McShann band, he got his number one hit, "Ain't Nobody's Business", the song which come to become look on his theme song. Within 1950 he got hits by owning deuce additional songs closely identified by owning him: "No Rollin' Blues" & "Big Fine Girl".

Witherspoon's style of blues became unstylish in the mid-1950s, but he returned to popularity by using his 1959 album, Jimmy Witherspoon at a Monterey Jazz Festival. He late recorded by using Ben Webster, Richard "Groove" Holmes, and T-Bone Walker, and toured in the 1970s with a highly regarded band of his own featuring Robben Ford. He continued performing into a 1980s.