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 mistaken, and that 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. As a teenager, Musselwhite moved to Memphis, Tennessee during the period when African-American music and white music were combining to give birh to rock and roll, rockabilly, and electric blues, and 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 could be not only seen in the local clubs and private parties but even approached person to person. 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 51 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 Delmark Records 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 even 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 naturally 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, Tom Waits' Mule Variations, and INXS' Suicide Blonde. He himself has won 14 W. C. Handy awards and 6 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, particularly when playing; by his own admission, he had never been on stage sober. In 1987, he finally quit drinking, and in 1990 signed with Alligator Records, which 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, 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."

Dec 20, 2005: Sad news; Memphis police are investigating the suspicious death of a famous Mid-South musicians Mother.

Memphis Police C-S-I teams spent hours processing the grizzly scene inside Ruth Maxine Musselwhite's home on Manhattan Avenue Tuesday morning trying to figure out how and how long ago she died.

Officers found Musselwhite's front door unlocked, her home burglarized and ransacked, and her body lying on the floor.

Police say it's possible she'd been there for weeks.

Ruth Musslewhite is the mother of Grammy Award-winning Memphis Bluesman Charlie Musselwhite, who issued a statement saying:

"Obviously this is a sad time for myself and my family. I have the utmost confidence in the Memphis Police department and am waiting to find out through their investigation the details of my mother's death."

Ruth Maxine Musselwhite's body was laid to rest Tuesday, Dec 27th. A very simple service was held for family and friends. Maxine was loved by her family and close friends and will surely be missed.