In 1909, Harelik's Russian-Jewish grandfather, Haskell Harelik—upon whom Harelik's 1985 play, The Immigrant, is based—immigrated to Galveston, Texas.

Mark Harelik was born in Hamilton, Texas. In 1987, he moved to Los Angeles where he co-wrote, with Randal Myler, Hank Williams: Lost Highway. In 1990, he worked in the Howard Korder play Search and Destroy and the william Ball play Cherry Orchard.

In 1997, he released a sequel, The Legacy, changing it from a true story to fiction. He has appeared in several other plays including Temptation (1989), The Heidi Chronicles (1991), Elmer Gantry (1991), Tartuffe (1999), Old Money (2000), The Hollow Lands (2000), Be Aggressive, The Beard of Avon (2001), Cyrano de Bergerac (2004). Harelik also played Dr. Paul Stickley in HBO's series Getting On, an American adaptation of the British sitcom of the same name.

Harelik has appeared in the films Election, Jurassic Park III, Eulogy and For Your Consideration; He was the voice of Rogers in The Swan Princess, and he has played parts on the television sitcoms Seinfeld, Wings, Grace Under Fire, Will & Grace, NCIS, Boy Meets World, Breaking Bad, Bones and The Big Bang Theory. He also played Sara Tancredi's Lawyer in Prison Break. He also appeared on the series finale of Cheers , in a 2002 episode of Joss Whedon's Angel as Count Kurushu, and "Counterpoint" an episode of Star Trek Voyager, playing Kashyk, a Devore inspector. He also appeared in five episodes of short-lived NBC series Awake. He appeared under his own name as an actor hired by the Heavenly host to play God in the TV series Preacher. Harelik appeared in the Broadway musical The Light in the Piazza. Harelik's play, The Immigrant, has been well-received, and was adapted into a musical of the same name.

In 2015, Harelik co-starred as Jamie Thompson's father in This Isn't Funny, and in 2017, he played baseball player Hank Greenberg in the film Battle of the Sexes.