He was born William Henry Jackson. Initially, he performed in minstrel shows and medicine shows. From the early 1920s into the 1930s, he played frequent club dates in Chicago and was noted for busking at Chicago's Maxwell Street Market. In August 1924, he recorded the commercially successful "Airy Man Blues" and "Papa's Lawdy Lawdy Blues" for Paramount Records. In April 1925, Jackson released his version of "Shave 'Em Dry". One of his subsequent tracks, "Salty Dog Blues", became his most famous song. Among his recordings are several in which he accompanied classic female blues singers, such as Ida Cox, Hattie McDaniel, and Ma Rainey.

According to the blues writer Bruce Eder, Jackson achieved "a musical peak of sorts in September of 1929 when he got to record with his longtime idol, Blind Arthur Blake, often known as the king of ragtime guitar during this period. 'Papa Charlie and Blind Blake Talk About It' parts one and two are among the most unusual sides of the late '20s, containing elements of blues jam session, hokum recording, and ragtime." A few more recordings for the Paramount label followed in 1929 and 1930. In 1934, Jackson recorded for Okeh Records, and the following year he recorded with Big Bill Broonzy. Altogether, Jackson recorded 66 sides during his career.