Tomei followed up As the World Turns, in 1987, with a role on the sitcom A Different World. Her breakthrough comedic performance came in My Cousin Vinny (1992), for which she won the Academy Award for Best Supporting Actress. After her Oscar win, she received a Screen Actor's Guild Award nomination for Outstanding Female Supporting Actor for Nick Cassavetes' Unhook the Stars. Next, she received an American Comedy Award nomination for Funniest Supporting Actress for Tamara Jenkins' Slums of Beverly Hills. She was nominated for a Satellite Award, as Best Supporting Actress for What Women Want. Former Saturday Night Live cast member Jay Mohr wrote in his book Gasping for Airtime that, as guest host in October 1994, Tomei insisted that a proposed skit about another actress not be used because she didn't like the idea of making fun of her, which displeased the writers and performers, given the show's penchant for satirizing celebrities.

In 1996, Tomei made a guest appearance on the sitcom Seinfeld, playing herself in "The Cadillac" two-part episode. In this episode, George attempts to get a date with Tomei through a friend of Elaine. She has also made an appearance on The Simpsons, as movie star Sara Sloane who falls in love with Ned Flanders. She received her first Golden Globe Award nomination and her second Academy Award-nomination for Best Supporting Actress in Todd Field's In The Bedroom (2001).

In 2003, Tomei appeared in the hit Anger Management with Adam Sandler and Jack Nicholson. In 2005, she was featured in an ad campaign for Hanes with the slogan "Look who we've got our Hanes on now", featuring various other celebrities including Michael Jordan, Jennifer Love Hewitt, Damon Wayans, Matthew Perry and, on Spanish-language advertising, Aracely Arambula and Pablo Montero. In 2006, Tomei had a recurring role on the TV series Rescue Me, playing Johnny's ex-wife Angie.

In 2007, she appeared in the comedy Wild Hogs alongside John Travolta, Tim Allen, William H. Macy and Martin Lawrence. The film was a blockbuster hit and was one of the highest grossing movies of 2007. She also starred in the Sidney Lumet-directed Before the Devil Knows You're Dead, opposite co-stars Philip Seymour Hoffman and Ethan Hawke. This role received extra attention because the usually modest Tomei had nude love scenes with both Hoffman and Hawke. In 2008, Tomei performed nude dance routines in another provocative role as a stripper, in the independent film The Wrestler opposite Mickey Rourke. She was nominated for a BAFTA, Golden Globe and Academy Award for this performance. Numerous critics heralded this performance as a standout in her career.

• The Night Job (2009) (in production)
• Untitled Duplass Brothers Project (2010) (filming) .... Molly
  
• The Wrestler (2008) .... Cassidy
• War, Inc. (2008) .... Natalie Hegalhuzen
• Before the Devil Knows You're Dead (2007) .... Gina Hanson
• Wild Hogs (2007) .... Maggie
  ... aka Blackberry (Philippines: English title: review title)
• Grace Is Gone (2007) .... Woman at Pool
• The Rich Inner Life of Penelope Cloud (2007) (TV) .... Penelope Cloud
• "Rescue Me" .... Angie (4 episodes, 2006)
  ... aka Rescue Me: FDNY (USA: complete title)
       - Karate (2006) TV episode .... Angie
       - Satisfaction (2006) TV episode .... Angie
       - Zombies (2006) TV episode .... Angie
       - Chlamydia (2006) TV episode .... Angie
• Danika (2006) .... Danika Merrick
• Factotum (2005) .... Laura
  ... aka Factotum (France)
  ... aka Factotum: A Man Who Performs Many Jobs (USA: long title)
• Loverboy (2005) .... Sybil
• Marilyn Hotchkiss Ballroom Dancing & Charm School (2005) .... Meredith Morrison
• Alfie (2004) .... Julie
• "Game Over" (2004) TV series (voice) .... Raquel Smashenburn (unaired pilot)
• Anger Management (2003) .... Linda
• "The Simpsons" .... Sara Sloane (1 episode, 2003)
       - A Star Is Born Again (2003) TV episode (voice) .... Sara Sloane
• The Wild Thornberrys Movie (2002) (voice) .... Bree Blackburn
• The Guru (2002) .... Lexi
  ... aka Gourou et les femmes, Le (France)
• Just a Kiss (2002) .... Paula
• Jenifer (2001) (TV) .... Nina Capelli