His first professional job in music was as a guitarist with blues legend Robert Nighthawk. In the 1940s Perkins played piano on radio broadcasts with Nighthawk and with Williamson on KFFA in Helena, Arkansas.

During the World War II years Perkins also drove a tractor on the Hopson plantation near Clarksdale, where an annual celebration is now held in his honor. In Clarksdale he later mentored a young Ike Turner on piano and began working with another prodigy, guitarist Earl Hooker.

Perkins first recorded as pianist on a Nighthawk session in Chicago in 1950. In 1953 Perkins recorded two versions of “Pinetop’s Boogie Woogie” when he and Earl Hooker did a session together for Sun Records in Memphis, but the tracks remained unissued until they appeared on a British album in the 1970s. In 1969, when Otis Span left the Muddy Waters band, Muddy called on Perkins to take his place.

International touring and recording with Muddy brought him widespread recognition, and he made his first album in 1976 for a French label, Black & Blue. In 1980 Perkins and other band members left Muddy and formed the Legendary Blues Band.

After recording two albums with the unit, Perkins embarked on his belated solo career. Although he did not have a full album under his own name in the United States until he was 75 years old (in 1988), during the next two decades he recorded more than 15 LPs and CDs as the reigning patriarch of blues piano. The Pinetop Perkins Blues Museum and Cultural Center was established in his honor by his hometown of Belzoni in 2010. On March 21, 2011, three weeks after receiving a Grammy award for Joined at the Hip, a CD he shared with former Muddy Waters bandmate Willie Smith, Perkins died in his sleep at his home in Austin, Texas.