Gershon attended New York University, where she studied drama and child psychology. She also attended the Circle in the Square Professional Theater School in New York, working with David Mamet and Harold Guskin. She is one of the founding members of the New York-based theater group Naked Angels.
She has appeared on Broadway three times, as Sally Bowles in the revival of Cabaret, in the revival of the sex farce Boeing-Boeing, and is currently playing Rosie Alvarez in the Broadway revival of Bye Bye Birdie at the Roundabout Theatre Company.
Her first acting venues were stage appearances in Camille and The Substance of Fire. She had a cameo role in The Cars 1984 video Hello Again along side Andy Warhol. Her break came with a bit part in 1986's Pretty in Pink which led to more substantial roles in Sweet Revenge with Nancy Allen and Cocktail, with Tom Cruise and Elisabeth Shue. Gershon also worked in TV, with a recurring role on Melrose Place playing a Heidi Fleiss-esque Hollywood madame. She won critical acclaim for her portrayal of Nancy Sinatra in the made-for-TV biopic Sinatra. In 1996, she played Corky, an ex-con who gets mixed up in a lesbian affair with Jennifer Tilly, in the mobster flick Bound. The following year, she costarred with John Travolta and Nicolas Cage in Face/Off.
Gershon is regarded as a gay icon because of her roles in movies such as Bound (in which she played a butch lesbian), Prey for Rock & Roll, and Showgirls (which is regarded as a camp classic). She was ranked #23 on the Maxim Hot 100 Women of 2004.
Gershon played Jew's harp on "I Can't Decide", a song on the Scissor Sisters 2006 release Ta-Dah. She also played Jew's harp on the song "I Do It For Your Love", Paul Simon's collaboration with Herbie Hancock on his album Possibilities, and on "Maria" from her album In Search Of Cleo. On television, she has recurring roles on HBO's Curb Your Enthusiasm (as a Hasidic dry cleaner), Rescue Me, and the U.S. dramedy series Ugly Betty (as Italian cosmetics mogul Fabia, the rival of Wilhelmina Slater). She also has served as the voiceover for Major League Baseball's "I Live For This" promotional campaign.
Gershon also appears in Lenny Kravitz's music video entitled "Again". She and her brother Dan are the authors of the children's book Camp Creepy Time. On September 10, 2008, Gershon appeared in a video on funnyordie.com, parodying former Republican vice presidential nominee Sarah Palin, titled "Gina Gershon Strips Down Sarah Palin" which she followed with "Gina Gershon Does Sarah Palin 2".
Gershon is set to guest-star on TBS' Glory Daze.