In the mid-1950s Guy began performing with bands in Baton Rouge, including with Big Papa Tilley and Raful Neal. While living there, he worked as a custodian at Louisiana State University. In 1957, he recorded two demos for a local DJ in Baton Rouge for Ace Records, but they were not issued at the time.
Soon after moving to Chicago on September 25, 1957, Guy fell under the influence of Muddy Waters. In 1958, a competition with West Side guitarists Magic Sam and Otis Rush gave Guy a record contract. Soon afterwards he recorded for Cobra Records. During his Cobra sessions, he teamed up with Ike Turner who helped him make his second record, "You Sure Can't Do" / "This Is The End", by backing him on guitar and composing the latter. After two releases from Cobra's subsidiary, Artistic, Guy signed with Chess Records.