He served in the House of Representatives from 1911 to 1931, and in the United States Senate from 1931 to 1941. Byrnes also served briefly as a Justice of the Supreme Court, a role which bored him at a time when the country was about to go to war. He only served in that position for a year and a half from 1941 to 1942.
Byrnes left the Supreme Court to head the New Deal's Economic Stablization Office upon the request of President Roosevelt. After Roosevelt's death, Harry Truman appointed him as Secretary of State in 1945, with whom he had a falling out. Byrnes left the post in 1947.
Opposed to desegregation (the issue had lost him his chance to run as Vice President), he became governor of South Carolina, serving from 1951 to 1955, and eventually switched allegiances to the Republican Party.