Spann began playing piano by age of eight, influenced by his local ivories stalwart, Friday Ford. At 14, he was playing in bands around Jackson, finding more inspiration in the 78s of Big Maceo Merriweather, who took the young pianist under his wing once Spann migrated to Chicago in 1946. Spann gigged on his own, and with guitarist Morris Pejoe, before hooking up with Muddy Waters in 1952.
Although he recorded periodically as a solo artist beginning in the mid 1950s, Spann was a full-time member of Waters' band from 1952 to 1968 before leaving to form his own band. In that period he also did session work with other Chess artists like Howlin' Wolf and Bo Diddley.
Spann's own Chess Records output was limited to a 1954 single, "It Must Have Been the Devil," that featured B. B. King on guitar. He recorded an session with the guitarist Robert Lockwood, Jr. and vocalist St. Louis Jimmy in 1960, which was issued on Otis Spann Is The Blues and Walking The Blues. A largely solo outing for Storyville Records in 1963 was recorded in Copenhagen. A set for the UK branch of Decca Records the following year found him in the company of Waters and Eric Clapton, and a 1964 album for Prestige followed, where Spann shared vocal duties with bandmate James Cotton.
The Blues is Where It's At, Spann's 1966 album for ABC-Bluesway, sounded like a live recording. It was a recording studio date, enlivened by enthusiastic onlookers that applauded every song (Waters, guitarist Sammy Lawhorn, and George "Harmonica" Smith were among the support crew). A Bluesway encore, The Bottom of the Blues followed in 1967 and featured Spann's wife, Lucille, helping out on vocals.
Several films of his playing are available on DVD, including the Newport Folk Festival (1960), while his singing is also featured on the American Folk Blues Festival (1963) and The Blues Masters (1966).
He was posthumously elected to the Blues Hall of Fame in 1980.