Pinetop Perkins was born in Belzoni, Mississippi in 1913. When he was still quite young he and his family moved to work on a plantation in Honey Island, Mississippi. He was raised there and at this time he learned to play the guitar, getting work at local parties and dances. In 1923, he learned to play the piano and got work at The Old Barrelhouse Honkeytonk in Honey Island. He continued to work outside of the music industry but always played gigs at the local bars in the Indianola area of Mississippi during the late twenties and early thirties, performing on both guitar and piano. Between 1941 and 1943, he worked with Boyd Gilmore in local gambling houses in Vance, Mississippi. After which he teamed with Robert Nighthawk and played on KFFA-radio in Helena, Arkansas. About this time  he was involved in a bar room brawl and his left arm was permanently injured, forcing him to concentrate solely on piano. He continued on into the mid 1940's with frequent tours all over the U.S. About this time he also teamed up with Sonny Boy Williamson (Alex Miller) and did some recording with King Biscuit Time which was also broadcast by KFFA-radio. In the mid 1950's through to the 1960's he toured and recorded with the Earl Hooker Band in Chicago.

In 1968 he replaced Otis Spann in the Muddy Waters Band and until the mid 1970's he toured almost continually with this band. Pinetop Perkins had his own, unmistakable sound. His right hand played horn lines while his left played bass. It was Pinetop, along with Pete Johnson, Meade Lux Lewis, Albert Ammons and Little Brother Montgomery, who provided the basic format and ideas from which countless swing bands derived their sound. Although he never performed swing, it was arguably his brand of boogie-woogie that eventually came to influence the structure of swing and, latterly, was a major influence on the development of Rock 'n Roll.