A farmer's son, Wallace worked his way through the University of Alabama Law School, graduating in 1942. Following military service in World War II, he served as assistant state's attorney (1946), after which he was elected to two terms in the state legislature. He was elected a judge of the Third Judicial Circuit of Alabama in 1953, and in 1958 he ran unsuccessfully for the governorship, losing the Democratic nomination (which was tantamount to election) to a segregationist candidate who had been endorsed by the Ku Klux Klan. Abandoning his moderate stance on integration, Wallace soon became known as the “fighting judge” owing to his defiance of the U.S. Commission on Civil Rights' investigation (civil rights movement) of discrimination in black voting rights. He held his judicial post until 1959.

Wallace won the governorship of Alabama in 1962 on a platform emphasizing segregation and economic issues. Within his first year in office he kept his pledge “to stand in the schoolhouse door” by blocking the enrollment of black students at the University of Alabama (June 1963). Declaring that the federal government was usurping state authority in the field of education, he yielded only in the face of the federalized National Guard. Further confrontations at Tuskegee, Birmingham, Huntsville, and Mobile made him a nationwide symbol of intransigence toward racial integration in the schools.

Though a segregationist during this period, Wallace could more accurately be termed a populist who seized on the issues that appealed to the majority of his white constituents. The civil-rights issue was a means for him to enter the national spotlight. Because Wallace was legally ineligible for reelection, his first wife, Lurleen, successfully ran for governor in 1966, but she died in office in 1968. That year Wallace was a vigorous but unsuccessful third-party candidate for the U.S. presidency, winning 13 percent of the vote and five Southern states as the nominee of the anti-liberal American Independent Party. He drew support mainly from white Southerners and blue-collar workers disenchanted with Democratic policies.

Wallace won Alabama's governorship again in 1970, but in 1972, while campaigning for the Democratic presidential nomination, he was wounded and left permanently paralyzed below the waist in an assassination attempt on May 15, 1972, at Laurel, Maryland. He was reelected to the governorship in 1974, and he again campaigned for the Democratic presidential nomination in 1976. In the 1980s Wallace renounced his segregationist ideology and sought reconciliation with civil rights leaders. In 1982 he sought a new term as governor and won the election with substantial support from black voters. He retired from politics in 1987 because of ill health.

While Wallace never achieved national office, many political analysts consider his presidential campaign to have been highly influential within American politics. Many (including Wallace himself) claimed that populist U.S. presidencies with anti-Washington leanings—such as those of Jimmy Carter and Ronald Reagan—were helped by ideas made familiar to the American public by George Wallace.