Lewis learned to play the piano by age six. Adopted at age twelve, he moved to a home in Detroit, Michigan. Growing up with the influences of the pioneer blues musicians until the advent of rock and roll, Lewis began to build a musical career in the 1950s, and in 1960 appeared at the Apollo Theatre in New York City.
In July 1961, his recording of "Tossin' and Turnin'" went to No.1 for seven weeks on the Billboard chart. It sold over one million copies and was awarded a gold disc. Later that year, he had a second Top Ten song, "One Track Mind", his only other major hit record, at No. 9.
"Tossin' And Turnin'", composed by Ritchie Adams and Malou Rene, was featured on the soundtrack for the 1978 film Animal House. The song was also covered by Steve Goodman, the Replacements, the Guess Who, Peter Criss, and Jimmy Sturr, among others. (The Ivy League's UK hit "Tossin' And Turnin", however, is a completely different song.)