While in prison, Malcolm joined the Nation of Islam (NOI) and adopted the surname "X" to acknowledge his unknown African ancestral name. Malcolm quickly became a leader with the NOI and was paroled in 1952, beginning a period of radical advocacy for black liberation.

In the 1960s, Malcolm X broke with the Nation of Islam, growing disillusioned with its leader Elijah Muhammed. During his 1964 pilgrimage to Mecca, he witnessed Muslims of "all colors, from blue-eyed blonds to black-skinned Africans" treat each other as equals in worship. Because of this, Malcolm X became convinced that Islam could be used as a means to achieve racial equality.

On February 21st, 1965, Malcolm was assassinated in New York City. Three Nation members were charged with the murder and given indeterminate life sentences. Two of these men, Muhammed Abdul Aziz and Khalil Islam, were exonerated in 2021 after a 22-month investigation by the Manhattan District Attorney found that evidence of their innocence, including FBI documents, was withheld at trial.

The Shabazz family are among those who have accused Louis Farrakhan of involvement in Malcolm X's assassination. In 1994, Betty Shabazz was asked if she thought Farrakhan had anything to do with her late husband's death. She replied "Of course, yes. Nobody kept it a secret. It was a badge of honor. Everybody talked about it, yes."

In the wake of his assassination, capitalist press vilified Malcolm X, while media in Africa, China, and Cuba lauded him as a hero and a martyr. The New York Times wrote that Malcolm X was "an extraordinary and twisted man" who "turn[ed] many true gifts to evil purpose", while Time magazine condemned him "an unashamed demagogue" whose "creed was violence."

In contrast, The Ghanaian Times identified Malcolm X as among "a host of Africans and Americans who were martyred in freedom's cause." In China, the People's Daily described him as a martyr killed by "ruling circles and racists" whose death illustrated that "in dealing with imperialist oppressors, violence must be met with violence."

In 2023, The Guardian reported that the Shabazz family announced their plans to sue the FBI, New York Police, and other agencies over Malcom X's death. Ilyasah Shabazz, the third daughter of Malcolm X and Betty Shabazz, announced that new information indicates federal and state agencies “conspired to and executed their plan to assassinate”. Ilyasah added "For years, our family has fought for the truth to come to light concerning his murder and we’d like our father to receive the justice that he deserves."