As an editor at the Call, Wilkins waged a campaign to defeat racist Senator Henry J. Allen. This effort caught the attention of Walter White (see), executive secretary of the N.A.A.C.P., who urged Wilkins to move to New York and become his chief assistant in 1931. As White had done, Wilkins went on assignment to investigate lynchings and working conditions for African-Americans in the South. His 1932 report, "Mississippi Slave Labor," is credited with bringing Congressional action to improve the working conditions for blacks in levee labor camps. In 1934, Wilkins replaced W.E.B. Du Bois (see) as editor of Crisis magazine, while continuing as a lecturer and organizer. In 1949 Wilkins chaired the National Emergency Civil Rights Mobilization and became acting executive secretary while White was on leave; on White's return, Wilkins was made head of internal affairs, and eventually succeeded White in 1955.

In the turbulent years of his leadership at the N.A.A.C.P., Wilkins followed the philosophy of Walter White, using legislation and the court system as weapons to fight for equality and constitutional justice. Among his most ardent causes were anti-lynching laws, fair housing laws, equal opportunity employment, and integration; he worked with Thurgood Marshall (see) on the 1954 Supreme Court school desegregation case and continued to be involved in its controversial aftermath during his tenure as head of the organization. Wilkins was criticized by more militant black groups who sought racial separatism, but he remained loyal to his convictions.

In 1929 Wilkins married Aminda (Minnie) Badeau, a social worker in St. Louis. In 1936, Mr. and Mrs. Wilkins moved from 307 West 136th Street to 409 Edgecombe Avenue, where they stayed until 1951. Wilkins lived in Queens village at the time of his death.