His elder brother was the bluesman Otis "Big Smokey" Smothers (died 1993), with whom he was sometimes confused.
Albert Abraham "Abe" Smothers was born in Tchula, Mississippi, learned to play the guitar at the age of 15, and relocated to Chicago two years later. He soon appeared on stage, playing with Arthur "Big Boy" Spires, Magic Sam, Otis Rush and Lazy Bill Lucas. In 1958 he joined up with Howlin' Wolf, and he accompanied Wolf in a recording session for Chess Records the following year. Tracks Smothers contributed to include "I've Been Abused", "Howlin' for My Darling". and "Mr. Airplane Man".
In 1961 he founded Little Smokey Smothers and the Pipeplayers. He later met Paul Butterfield and became a founding member of the Paul Butterfield Blues Band. He was replaced in the band by Elvin Bishop but developed a friendship that lasted a lifetime. Throughout the 1960s Smothers appeared with Buddy Guy, James Cotton, Earl Hooker, and Junior Wells. Musical opportunities dried up in the 1970s, and Smothers worked in construction. After a break of several years, he recorded again in 1979, on Mojo Buford's album Chicago Blues Summit. In the 1980s he was with the Legendary Blues Band and contributed to their 1989 album Woke Up with the Blues.
In 1993, Bishop was a guest artist on Smothers's first solo album, Bossman! The Chicago Blues of Little Smokey Smothers, released by the Dutch label Black Magic. Smothers's cousin Lee "Shot" Williams also played on the album. Bishop and Smothers performed at the 1993 Chicago Blues Festival.
Alligator Records issued That's My Partner in 2000, a live album recorded in San Francisco, in which Smothers reunited with Bishop. Smothers also performed at the 2000 Chicago Blues Festival. He appeared in Martin Scorsese's 2003 television series The Blues, which contained excerpts from his live show. In 2006 Smothers and Bishop played at the Ground Zero club in Clarksdale, Mississippi.
In 2009, Bishop compiled the benefit album Chicago Blues Buddies, incorporating recordings he made with Smothers dating back to 1992. Proceeds from the album helped to pay for Smothers's medical expenses.