In January 1946, Malcolm Little was arrested and charged with grand larceny and breaking and entering. He was promptly sentenced to prison, and would live behind bars until his release in August 1952. At the Concord Reformatory Prison in Massachusetts, Malcolm was introduced to a black nationalist Islamic sect, the Nation of Islam (NOI), by his brother Reginald. Joining the NOI while incarcerated, Malcolm corresponded frequently with the sect's leader, Elijah Muhammad (formerly Elijah Poole). The NOI's core tenets, including the racial supremacy of black people and the idea that whites are literally "devils" were extremely attractive to Malcolm, whose own personal and family's experiences and lives had been shattered by white racism. Paroled from prison in August 1952, Malcolm Little became Malcolm X. The surname "X" represented the true name of his African ancestors. In early 1953 Malcolm X lived briefly in the home of Elijah Muhammad. He quickly rose up the leadership hierarchy of the NOI. Malcolm X was named minister of the newly established Boston Temple No. 11 in the fall of 1953. He became minister of New York's Temple No. 7 in June 1954, which he would lead for the next ten years.

In the decade of the 1950s, Malcolm X was primarily responsible for the rapid growth of the NOI, and its prominence as a cultural and spiritual force within black America. A powerful, attractive and charismatic speaker, Malcolm X traveled extensively throughout the country on behalf of the Nation of Islam. Malcolm X initiated and directed the development of new temples in many cities, and established a national newspaper, Muhammad Speaks. A 1959 television documentary on the NOI, with the provocative title, "The Hate that Hate Produced," brought the black nationalist sect into national prominence. That same year Malcolm X traveled extensively on behalf of Elijah Muhammad, visiting Egypt, Iran, Syria, Ghana, Nigeria and Sudan. By the late 1950s and early 1960s he became actively involved in protesting cases of police brutality against "Black Muslims," which was the general name the media gave to NOI members.

Malcolm X constantly emphasized that African Americans had to break from their psychological, cultural and political dependence on white values and institutions. "Self determination" as a viable concept meant that blacks had to construct strong institutions that permitted them to negotiate with the "white establishment." The philosophy of racial assimilation, he believed, would never empower the masses of poor and working black people. In The Autobiography of Malcolm X, he observed: "The American black man should be focusing his every effort toward building his own businesses, and decent homes for himself. As other ethnic groups have done, let the black people, wherever possible, however possible, patronize their own kind, hire their own kind, and start in those ways to build up the black race's ability to do for itself. That's the only way the American black man is ever going to get respect!"

In his personal life in 1956, Malcolm X met Betty Sanders, a new convert who had joined Temple No. 7. In January, 1958, Malcolm X proposed marriage to Betty X from a gas station telephone in Detroit. Two days later the young couple was married by a white Justice of the Peace in Lansing, Michigan. Returning to Harlem, Temple No. 7 members were shocked their Minister Malcolm X and fellow member Betty X had just married. The newlyweds moved into a small two-family flat in Queens, New York. Malcolm X and Betty (Shabazz) had six daughters, and despite his extensive travels and financial constraints, maintained a close relationship.

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