After graduating (1923) from Clemson College (now Clemson University) in South Carolina, Thurmond taught school until 1929, when he became superintendent of education for Edgefield county. During this time he also began studying law and in 1930 was admitted to the bar. He then served as a city and county attorney until 1938 and was also a state senator (1933–38) and a circuit court judge (1938–41). Thurmond emerged from his military service in World War II a highly decorated lieutenant colonel. He was elected governor of South Carolina in 1946 and proceeded to initiate several liberal reforms, including a notable expansion of the state educational system. At the Democratic National Convention of 1948, however, Thurmond led the bolt of Southern delegates angry over the civil rights plank in the party platform. The Southerners formed the States' Rights Democratic Party—popularly known as the Dixiecrats (Dixiecrat)—and nominated Thurmond as their presidential candidate. He won 39 electoral votes.

Elected by write-in vote to the Senate in 1954, Thurmond quickly established himself in the Southern conservative mold as a vigorous champion of increased military power and spending and an archfoe of civil rights legislation. He was reelected in 1960, but in 1964 he again left the Democratic Party in support of the conservative Republican presidential nominee, Barry Goldwater (Goldwater, Barry). Reelected as a Republican to seven consecutive terms, Thurmond continued to seek Southern conservative support for the GOP. In 1996 he became the oldest person to serve in Congress and the following year became the longest-serving U.S. senator; he held the latter distinction until 2006, when he was surpassed by Robert C. Byrd of West Virginia.

Soon after Thurmond's death it was revealed that at the age of 22 he had fathered a daughter out of wedlock. The mother was a 16-year-old African American maid who worked for his family.