He began his law career in a private practice built upon civil rights issues. He worked for the Baltimore branch of the N.A.A.C.P. and then became an assistant to his mentor, the N.A.A.C.P.'s special counsel Charles Hamilton Houston, succeeding him in that post in 1938. During the next phase of his career as director-counsel of N.A.A.C.P. Legal Defense and Educational Fund, Marshall was involved in several landmark cases, using the courts to combat racial inequality and to fight for full citzenship rights for African-Americans: in 1938 he wrote the brief in the case which led to admission of a black student into University of Missouri Law School; in 1944 he fought for the right of blacks to vote in primary elections in Texas; in 1948 he was successful in getting restrictive housing covenants overturned as unconstitutional; in 1950 he won for black students the right to admission in the law school of the University of Texas; and in 1954, in Brown vs. Board of Education of Topeka, Kansas, Marshall won his greatest legal victory, ending unfair "separate but equal" racial segregation in public education and beginning the process of school desegregation in 21 states. The N.A.A.C.P. awarded him the Spingarn Medal in 1946.

In 1961 President John F. Kennedy appointed Marshall judge of U.S. District Court for the Second Judicial Circuit. After spending four years on District Court, Marshall was named U.S. Solicitor-General. In 1967 he was appointed to the U.S. Supreme Court by President Lyndon Johnson. His record was outstanding; before his own appointment to the Supreme Court, he had argued thirty-two cases before the High Court and won twenty-nine of them. As a Supreme Court Justice, Marshall, as his New York Times obituary points out, often found that "his most powerful voice was in dissent." One of his strongest stances was opposition to the death penalty in all cases. He retired from the Supreme Court in 1991.

Marshall maintained a residence at 409 Edgecombe Avenue from about 1940 until 1957. He married his first wife, the former Vivian Burey, in 1929; she died in 1955. Later that year he married Cecilia Suyat, with whom he had two sons: Thurgood Jr., the legislative affairs co-ordinator for the Office of the Vice President (Albert Gore), and John, a member of the Virigina State Police.