He earned a degree in speech at West Virginia University, and earned his master's degree in theater from Catholic University of America (CUA) in Washington, D.C. After graduation, he toured with numerous improvisational companies and became much involved with regional theatre, making his professional debut in the play The Rose Tattoo during 1965.

[4][5] Later that year Sarandon moved to New York City, where he obtained his first television role as Dr. Tom Halverson for the series The Guiding Light (1973–1974).

He appeared in the primetime television movies The Satan Murders (1974) and Thursday's Game before obtaining the role in Dog Day Afternoon (1975), a performance which earned him nominations for Best New Male Star of the Year at the Golden Globes and the Academy Award for Best Supporting Actor.

One of his most endearing roles onscreen is that of Prince Humperdinck in Rob Reiner's 1987 movie The Princess Bride, though he also has had supporting parts in many other successful films, including his lead turn in the original horror classic Child's Play (1988).

He also played Jack Skellington, the main character of Tim Burton's animated Disney movie The Nightmare Before Christmas (1993), and has since reprised the role in other productions, including the Disney/Square video games Kingdom Hearts and Kingdom Hearts II and the Capcom sequel to the original movie, Oogie's Revenge.

In 1991 he performed on Broadway in the short-lived musical Nick & Nora (based on the movie The Thin Man) with Joanna Gleason, the daughter of Monty Hall.

In 2016 he performed in the Off-Broadway production of the Dave Malloy musical Preludes as Anton Chekhov, Tchaikovsky, Alexander Glazunov, Leo Tolstoy, Tsar Nicholas II, and The Master.

[1][8] The couple met while performing in Broadway's short-lived 1991 musical Nick & Nora; they returned to the stage together in 1998's Thorn and Bloom.