Hollings was born in Charleston, South Carolina. He went to The Citadel and received a B.A. in 1942; he later attended the University of South Carolina and received a LL.B. in 1947. He is married to Rita "Peatsy" Liddy and has four children. He is a Lutheran.

Hollings served as an officer in the U.S. Army's 323rd and 457th Artillery units from 1942 to 1945, during World War II, and was awarded the Bronze Star. He was first elected to the South Carolina House of Representatives in 1948; he was subsequently elected lieutenant governor of the state in 1955 and Governor in 1958. He was governor from 1959 until 1963. During his governorship he ordered the Confederate Flag to be raised over the state capital to commemorate the 100th anniversary of South Carolina's succession from the union and to protest the growing civil rights movement. He sought the Democratic nomination for a seat in the U.S. Senate in 1962, but lost to Olin D. Johnston.

Johnston died on April 18, 1965, however, and Hollings was elected to fill his Senate seat in a 1966 special election. He was subsequently elected to a full six-year term in 1968 and served for six full terms. For 37 years (until 2003), he served alongside Republican Strom Thurmond, making them the longest-serving Senate duo ever. The two generally had a good relationship despite their sharp philosophical differences. Only Thurmond, Robert Byrd, Ted Kennedy, Daniel Inouye, Carl Hayden and John Stennis served longer in the Senate.

He unsuccessfully sought the Democratic nomination for President of the United States in the presidential election of 1984.

Hollings would become popular for the wrong reasons among fans of Beavis and Butt-Head after he said to Janet Reno; "We've got this...what is it...Buffcoat and Beaver or Beaver and something else. I haven't seen it, I don't watch it, but whatever it is, it was at 7, Buffcoat, and they put it on now at 10:30". Since the quote was made, the act of mispronouncing Beavis and Butt-Head's names became a running gag on the show.

On August 4, 2003, he announced that he would not run for re-election in November 2004. Republican Jim DeMint succeeded him.

As a senator, Hollings was noted for his support for legislation that was in the interests of the established media distribution industry (such as the proposed "Consumer Broadband and Digital Television Promotion Act") and was described by opponents as 'Hollywood Hollings' or the 'Senator from Disney'. Hollings also sponsored the Online Personal Privacy Act (S. 2201).

Hollings was generally considered to be a liberal supportive of many civil rights bills. He voted for re-authorizing the Voting Rights Act in 1982. He was a staunch fiscal conservative, and was one of the namesakes for the Gramm-Rudman-Hollings Act, an attempt to put limits on government spending.

Hollings penned a controversial editorial in the May 6, 2004 Charleston Post and Courier, where he argued that Bush invaded Iraq because "spreading democracy in the Mideast to secure Israel would take the Jewish vote from the Democrats."