Gershon moved to New York City from Boston to attend 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. Her first acting venues were stage appearances in Camille and The Substance of Fire. Her break came with a bit part in 1986's Pretty in Pink, and then a bigger part in Cocktail, with Tom Cruise. Gershon also worked in TV, with a recurring role on Melrose Place. 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). At the same time, her sultry good looks and frequent nude appearances in other films have also gained her a substantial heterosexual male fan base. She was ranked #51 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. 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. She and her brother Dann 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".

• Love Ranch (2009) (post-production)
  
• "Numb3rs" .... Danielle Hill (1 episode, 2009)
  ... aka "Num3ers" (USA: promotional title)
       - 12:01 AM (2009) TV episode .... Danielle Hill
• "Life on Mars" .... Rita (1 episode, 2009)
       - Coffee, Tea, or Annie (2009) TV episode .... Rita
• Beer for My Horses (2008) .... Cammie
• Just Business (2008) (V) .... Marty Jameson
• P.S. I Love You (2007) .... Sharon
• "Curb Your Enthusiasm" .... Anna (2 episodes, 2004-2007)
       - The Anonymous Donor (2007) TV episode .... Anna
       - The Survivor (2004) TV episode .... Anna
• "Rescue Me" .... Valerie (6 episodes, 2007)
  ... aka "Rescue Me: FDNY" (USA: complete title)
       - Yaz (2007) TV episode .... Valerie
       - Keefe (2007) TV episode (credit only) .... Valerie
       - Cycle (2007) TV episode .... Valerie
       - High (2007) TV episode .... Valerie
       - Animal (2007) TV episode .... Valerie
        (1 more)
• "Psych" .... Emilina Saffron (1 episode, 2007)
       - American Duos (2007) TV episode .... Emilina Saffron
• "Ugly Betty" .... Fabia (3 episodes, 2006-2007)
       - East Side Story (2007) TV episode .... Fabia
       - I'm Coming Out (2007) TV episode .... Fabia
       - Pilot (2006) TV episode .... Fabia
• What Love Is (2007) .... Rachel
• "The Batman" .... Catwoman / ... (5 episodes, 2004-2007)