Born Frank Seals in Arkansas in 1942, Seals learned to play the drums as a child but switched to the guitar in his teens. In 1971, he moved to Chicago, where he played with such older bluesmen as Hound Dog Taylor, Buddy Guy, and Junior Wells. The newly created Alligator Records released his first recording in 1973; his second album, Midnight Son, helped establish him as a major figure.

Seals recorded a total of eight albums for Alligator; his last recording, Letting Go, was released by Telarc in 2000. He performed for the last time in October.