In late 1950s New Orleans, Dr. John originally concentrated on guitar and he gigged with local bands including Mac Rebennack and the Skyliners, (Paul Staele/Dennis "Bootsie" Cuquet, drums; Earl Stanley, bass; Charlie Miller, trumpet; Charlie Maduell, sax; Roland "Stone" LeBlanc, vocals), Frankie Ford and the Thunderbirds, and Jerry Byrne and the Loafers. He had a regional hit with a Bo Diddley-influenced instrumental called "Storm Warning" on Rex Records in 1959. During these days he was an A&R man producing, with Charlie Miller, monophonic singles on 45s for Johnny Vincent and Joe Corona for such local labels as ACE, RON, RIC and others. For these sessions he oversaw A&R and the rhythm section while Miller wrote the horn arrangements and headed up the horns. It was a productive team until Miller decided to move to New York and to study music formally.
Rebennack's career as a guitarist came to an end when his left ring finger was injured by a gunshot while he was defending singer/keyboardist Ronnie Barron, his bandmate, Jesuit High Schoolclassmate, and longtime friend. After the injury, Rebennack concentrated on bass guitar before making piano his main instrument; pianist Professor Longhair was an important influence on Rebennack's piano-playing style.
He moved to Los Angeles in 1963 where he became a "first call" session musician on the booming Los Angeles studio scene in the 1960s and 1970s, providing backing for Sonny & Cher (and some of the incidental music for Cher's first film, Chastity), and for Canned Heat on their albums Living the Blues (1968) Future Blues (1970), and Freak Out! for Frank Zappa and the Mothers of Invention(1966); along with many other acts.