By 1931 he had moved to Chicago, where he first recorded as Bumble Bee Slim for Paramount Records. The following year his song, "B&O Blues", was a hit for Vocalion Records, inspiring a number of other railroad blues and eventually becoming a popular folk song. Over the next five years he recorded over 150 songs for the Decca, Bluebird and Vocalion labels, often accompanied by other musicians such as Big Bill Broonzy, Peetie Wheatstraw, Tampa Red, Memphis Minnie, and Washboard Sam.
In contrast to the emotive songs of many earlier blues performers, Slim's material and vocal delivery were relaxed, light and often humorous, an approach welcomed by many listeners during the Great Depression. He became one of the best-selling blues artists of the 1930s, and his recordings exemplify the beginnings of the Chicago blues, retaining elements of earlier styles while anticipating later more polished urban sounds.
In 1937 he returned to Georgia, then relocated to Los Angeles, California, in the early 1940s, apparently hoping to break into motion pictures as a songwriter and comedian. During the 1950s he recorded several albums, but these had little impact. He recorded his last album in 1962 for the Pacific Jazz label.
He continued to perform in clubs around Los Angeles until his death in 1968.