He was born in Osceola, Arkansas where his father, Jim "Son" Seals, owned a small juke joint. He began performing professionally by the age of 13, first as a drummer with Robert Nighthawk, and later as a guitarist. At age 16, he began to play at the T-99, a local upper echelon club, with Walter Jefferson, “Little Walter”, who was his brother in law. At the T-99, he played with many other musicians, such as Albert King, Rufus Thomas, Bobby Bland, Junior Parker, and Rosco Gordon. Their varying styles contributed to the development of Seals' own playing techniques. While playing at the T-99, he was also introduced to country-western music by Jimmy Grubbs, who would ask Seals to gig with his group every now and then on both drums and guitar. At 19 years old, he formed his own band to fill in at a local club in Osceola called the Rebel Club. Shortly thereafter, a man from Little Rock, Arkansas came to find “Little Walter” for a gig at his club, but when he turned it down the offer went to Seals. The band members were “Old man Horse” (Johnny Moore) on piano, Alvin Goodberry on either drums, guitar, bass, or piano, “Little Bob” (Robinson) on vocals, and Walter Lee “Skinny Dynamo” Harris on piano. The band’s name was “Son Seals and the Upsetters.”
In 1971, Seals moved to Chicago. His career took off after he was discovered by Bruce Iglauer of Alligator Records at the 'Flamingo Club' in Chicago's South Side. His debut album, The Son Seals Blues Band, was released in 1973. The album included "Your Love Is Like a Cancer" and "Hot Sauce". Seals followed up with 1976's Midnight Son and 1978's Live and Burning. He continued releasing albums throughout the next two decades, all but one on Alligator Records. These included Chicago Fire (1980), Bad Axe (1984), Living in the Danger Zone (1991), Nothing But the Truth and Live-Spontaneous Combustion (1996). He received the W.C. Handy Award in 1985, 1987, and 2001.
Author Andrew Vachss was a friend of Seals, and used his influence to promote Seals' music. Vachss gave Seals several cameo appearances in his novels and co-wrote songs with him for his 2000 album, Lettin' Go. Vachss dedicated the novel Mask Market to Seals' memory.
In 2002, Seals was featured on the Bo Diddley tribute album, Hey Bo Diddley - A Tribute!, performing the song "My Story" (aka "Story of Bo Diddley").
Seals had a number of problems in his life. He survived all but one of his fourteen siblings, and in 1997 he was shot in the jaw by his wife, sustaining injuries which required reconstructive surgery. Also, in 1999 part of his left leg was amputated, due to complications from diabetes. He lost belongings in a fire that destroyed his home while he was away performing live, and several of his prized guitars were stolen from his home. After his health problems Seals used a number of different accompanying bands, such as James Soleberg's, Jimmy Vivino's, and Big Jim Kohler's, while on the road.
The band Phish performed Seals' song "Funky Bitch", and brought him on stage on multiple occasions.
Seals died in 2004, at the age of 62, from complications of diabetes; he was survived by his sister and fourteen children.