Born in Jackson, Mississippi, United States, Spann became known for his distinct piano style. Born to Frank Houston Spann and Josephine Erby. One of five children - three boys and two girls. His father played piano, non professionally, while his mother had played guitar with Memphis Minnie. Spann began playing piano by age of eight, influenced by his local ivories stalwart, Friday Ford.

At the age of 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. Other sources say that he moved to Chicago when his mother died in 1947 playing the Chicago club circuit and working as a plasterer.

Spann gigged on his own, and with guitarist Morris Pejoe, working a regular spot at the Tic Toc Lounge before hooking up with Muddy Waters in 1952. Although he recorded periodically as a solo artist, Spann was a full-time member of the Muddy Waters band from 1952 to 1968.

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" / "Five Spot", which featured B.

B. King and Jody Williams on guitars.

He recorded a session with the guitarist Robert Lockwood, Jr. and vocalist St.

Louis Jimmy in New York on August 23, 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 UK Decca Records the following year found him in the company of Muddy 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 (Muddy 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 Jenkins Spann (June 23, 1938 – August 2, 1994), helping out on vocals.

In the late 1960s, he appeared on albums with Buddy Guy, Big Mama Thornton, Peter Green and Fleetwood Mac. 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).