Cooke had 29 top-40 hits in the U.S. between 1957 and 1964. Major hits like "You Send Me", "A Change Is Gonna Come", "Chain Gang", "Wonderful World", and "Bring It on Home to Me" are some of his most popular songs. Cooke was also among the first modern black performers and composers to attend to the business side of his musical career. He founded both a record label and a publishing company as an extension of his careers as a singer and composer. He also took an active part in the American Civil Rights Movement.

On December 11, 1964, Cooke was shot dead by the manager of the Hacienda Motel in Los Angeles, California at the age of 33. At the time, the courts ruled that Cooke was drunk and distressed, and the manager killed Cooke in what was later ruled a justifiable homicide. Since that time, the circumstances of his death have been widely questioned.

Cooke was born in Clarksdale, Mississippi. He later added an "e" onto the end of his name, though the reason for this is disputed. He was one of eight children of Annie Mae and the Reverend Charles Cook, a Baptist minister. He had a brother, L.C., who some years later would become a member of the Doo Wop band Johnny Keyes and the Magnificents. The family moved to Chicago in 1933. Cooke attended Wendell Phillips Academy High School in Chicago, the same school that Nat "King" Cole had attended a few years earlier.

Cooke began his career singing gospel with his siblings in a group called The Singing Children. He first became known as lead singer with the Highway QC's as a teenager. In 1950, Cooke replaced gospel tenor Reubert H. Harris as lead singer of the landmark gospel group The Soul Stirrers. Under Cooke's leadership, the group signed with Specialty Records and recorded the hits "Peace in the Valley", "How Far Am I From Canaan?", "Jesus Paid the Debt" and "One More River".

His first pop single, "Lovable" (1956), was released under the alias "Dale Cooke" in order not to alienate his gospel fan base (he sang with the Soul Stirrers until 1957); there was a considerable stigma against gospel singers performing secular music. However, it fooled no one - Cooke's unique and distinctive vocals were easily recognized. Art Rupe, head of Specialty Records, the label of the Soul Stirrers, gave his blessing for Cooke to record secular music under his real name, but he was unhappy about the type of music Cooke and producer Bumps Blackwell were making. Rupe expected Cooke's secular music to be similar to that of another Specialty Records artist, Little Richard. When Rupe walked in on a recording session and heard Cooke covering Gershwin, he was quite upset. After an argument between Rupe and Blackwell, Cooke and Blackwell left the label.

In 1957, Cooke appeared on ABC's The Guy Mitchell Show. That same year, he signed with Keen Records. His first release was "You Send Me", the B-side of his first Keen single (the A-side was a reworking of George Gershwin's "Summertime") which spent six weeks at #1 on the Billboard R&B chart. The song also had mainstream success, spending three weeks at #1 on the Billboard pop chart.

In 1961, Cooke started his own record label, SAR Records, with J.W. Alexander and his manager, Roy Crain. The label soon included The Simms Twins, The Valentinos, Bobby Womack, and Johnnie Taylor. Cooke then created a publishing imprint and management firm, then left Keen to sign with RCA Victor. One of his first RCA singles was the hit "Chain Gang". It reached #2 on the Billboard pop chart and was followed by more hits, including "Sad Mood", "Bring it on Home to Me" (with Lou Rawls on backing vocals), "Another Saturday Night" and "Twistin' the Night Away".

Like most R&B artists of his time, Cooke focused on singles; in all he had twenty-nine top-40 hits on the pop charts, and more on the R&B charts. In spite of this, he released a well received blues-inflected LP in 1963, Night Beat, and his most critically acclaimed studio album Ain't That Good News, which featured five singles, in 1964.

Cooke died at the age of thirty-three on December 11, 1964, at the Hacienda Motel at 9137 South Figueroa Street in Los Angeles, California. Bertha Franklin, manager of the motel, told police that she shot and killed Cooke in self-defense because he had threatened her. Police found Cooke's body in Franklin's apartment-office, clad only in a sports jacket and shoes, but no shirt, pants or underwear. The shooting was ultimately ruled a justifiable homicide. His funeral was held in Chicago at A.R Leak Funeral Home, where thousands of fans had lined up for over 4 city blocks to view his body. Cooke was interred in the Forest Lawn Memorial Park Cemetery in Glendale, California.

Some posthumous releases followed, many of which became hits, including "A Change Is Gonna Come", an early protest song that is generally regarded as his greatest composition. After Cooke's death, his widow, Barbara, married Bobby Womack. Cooke's daughter, Linda, later married Bobby's brother, Cecil.