Chandler served in the state senate of Kentucky in 1929. He served as Governor from 1935 to 1939, but resigned that office to be appointed US Senator in 1939; he was then elected to the Senate in 1940 to fill out the term and he was re-elected in 1942. He served as governor of Kentucky again from 1955 to 1959. He was a member of the Democratic Party.
He resigned from the Senate to become Commissioner of Major League Baseball in 1945 and remained in that post to 1951; during his service in this office he oversaw the initial steps toward integration of the major leagues, beginning with the debut of Jackie Robinson with the Brooklyn Dodgers in 1947.