Balaban has appeared in the Christopher Guest comedies Waiting for Guffman (1996), Best in Show (2000), A Mighty Wind (2003), and For Your Consideration (2006) and in the Wes Anderson films Moonrise Kingdom (2012), The Grand Budapest Hotel (2014), Isle of Dogs (2018) and The French Dispatch (2021).

Sam had been an early partner of Bob's uncles Abe, Barney, John, and Max in forming Balaban and Katz.

In the 1970s, he appeared as Grady Garrett on an episode of Room 222, Orr in Catch-22, Elliot the Organizer in The Strawberry Statement,[11] and the interpreter David Laughlin in the 1977 Steven Spielberg science fiction film Close Encounters of the Third Kind.

During the 1980s he appeared in films including Ken Russell's Altered States (1980) and the 1984 2001: A Space Odyssey sequel 2010 (as Dr. Chandra, the creator of HAL 9000).

Balaban had supporting roles in films such as Absence of Malice, Bob Roberts, Deconstructing Harry, Ghost World, The Majestic, Lady in the Water, and Christopher Guest's Waiting for Guffman, Best in Show, A Mighty Wind, and For Your Consideration.

In 1999, Balaban made a guest appearance in the sitcom Friends as Phoebe Buffay's father Frank in "The One with Joey's Bag".

Alongside Morgan Freeman and John Lithgow, Balaban appeared onstage in September 2011 as Judge Vaughn Walker in the Broadway debut of the play 8, which depicts the federal trial that overturned California's Prop 8 ban on same-sex marriage.

[12] The production was held at the Eugene O'Neill Theatre to raise money for the American Foundation for Equal Rights.

[13][14] In 2012, Balaban directed four episodes of the Showtime series Nurse Jackie,[15] and voiced the audiobook version of Warren Littlefield's autobiography, Top of the Rock: Inside the Rise and Fall of Must See TV.