Musselwhite was born in the rural hill country of Mississippi. He has said that he is of Choctaw descent, and he was born in a region originally inhabited by the Choctaw. However, in a 2005 interview, he said his mother had told him he was actually Cherokee. His family considered it normal to play music, with his father playing guitar and harmonica, his mother playing piano, and a relative who was a one-man band. At the age of three, Musselwhite moved to Memphis, Tennessee.
His family considered it normal to play music, with his father playing guitar and harmonica, his mother playing piano, and a relative who was a one-man band. At the age of three, Musselwhite moved to Memphis, Tennessee. When he was a teenager, Memphis experienced the period when rockabilly, western swing, electric blues, and some forms of African American music were combining to give birth to rock and roll. The period featured legendary figures such as Elvis Presley, Jerry Lee Lewis, and Johnny Cash, as well as minor legends such as Gus Cannon, Furry Lewis, Will Shade, Royal Bell, Memphis Willie B., Johnny Burnette, Red Roby, Abe McNeal, and Slim Rhodes. Musselwhite supported himself by digging ditches, laying concrete and running moonshine in a 1950 Lincoln. This environment was Musselwhite's school for music as well as life, and he acquired the nickname "Memphis Charlie."
In true bluesman fashion, Musselwhite then took off in search of the rumored "big-paying factory jobs" up the "Hillbilly Highway", legendary Highway 61 to Chicago, where he continued his education on the South Side, making the acquaintance of even more legends including Muddy Waters, Junior Wells, Sonny Boy Williamson, Buddy Guy, Howlin' Wolf, Little Walter, and Big Walter Horton. Musselwhite immersed himself completely in the musical life, living in the basement of, and occasionally working at Jazz Record Mart (the record store operated by Delmark Records founder Bob Koester) with Big Joe Williams and working as a driver for an exterminator, which allowed him to observe what was happening around the city's clubs and bars. He spent his time hanging out at the Jazz Record Mart at the corner of State and Grand and the nearby bar, Mr. Joe's, with the city's blues musicians, and sitting in with Big Joe Williams and others in the clubs, playing for tips. There he forged a lifelong friendship with John Lee Hooker; though Hooker lived in Detroit, Michigan, the two often visiting each other, and Hooker serving as best man at Musselwhite's wedding. Gradually Musselwhite became well known around town.
In time, Musselwhite led his own blues band, and, after Elektra Records' success with Paul Butterfield, he released the classic Stand Back! album in 1966 on Vanguard Records (as "Charley Musselwhite"), to immediate and great success. He took advantage of the clout this album gave him to move to San Francisco, where, instead of being one of many competing blues acts, he held court as the king of the blues in the exploding countercultural music scene, an exotic and gritty figure to the flower children. Musselwhite even convinced Hooker to move out to California.
Since then, Musselwhite has released over 20 albums, as well as guesting on albums by many other musicians, such as Bonnie Raitt's Longing in Their Hearts and The Blind Boys of Alabama's Spirit of the Century, both winners of Grammy awards. He also appeared on Tom Waits' Mule Variations and INXS' Suicide Blonde. He himself has won 14 W. C. Handy awards and six Grammy nominations, as well as Lifetime Achievement Awards from the Monterey Blues Festival and the San Javier Jazz Festival in San Javier, Spain, and the Mississippi Governor's Award for Excellence in the Arts.
In 1979, Musselwhite recorded The Harmonica According to Charlie Musselwhite in London for Kicking Mule Records, intended to go with an instructional book; the album itself became so popular that it has been released on CD.
Unfortunately, Musselwhite, as with many of his peers, fell victim to alcoholism; by his own admission, he had never been on stage sober until after he stopped drinking entirely in 1987.
In 1990 Musselwhite signed with Alligator Records, a step led to a resurgence of his career.
Over the years, Musselwhite has branched out in style. His 1999 recording, Continental Drifter, is accompanied by Quarteto Patria, from Cuba's Santiago region, the Cuban music analog of the Mississippi Delta. Because of the political differences between Cuba and the United States, the album was recorded in Bergen, Norway, with Musselwhite's wife ironing out all the details.
Musselwhite believes the key to his musical success was finding a style where he could express himself. He has said, "I only know one tune, and I play it faster or slower, or I change the key, but it's just the one tune I've ever played in my life. It's all I know."
His past two albums, Sanctuary and Delta Hardware have both been released on Real World Records.