His musical career began as a session musician in the New Orleans in the 1950s. Early on he also played guitar and was often known as Mac Rebennack. He switched to the piano after his index finger was nearly shot off protecting his bandmate, Jesuit High School classmate, and longtime friend Ronnie Barron. He gained fame beginning in the late 1960s and early 1970s, with music that combined New Orleans-style rhythm and blues with psychedelic rock and stage shows that bordered on voodoo religious ceremonies, including elaborate costumes and headdress. For a time he was billed as "Doctor John, The Night Tripper". The name "Dr. John" came from a legendary Louisiana voodoo practictioner from the start of the 19th century.
He is perhaps best known for his 1973 song, "Right Place, Wrong Time." Dr. John has also done vocals for Popeye's Chicken's "Luv dat Chicken..." jingle.