After moving to L.A., Amick appeared on Star Trek: The Next Generation as well as in The Borrower (1991). Amick got her first break when director David Lynch chose her to play waitress Shelly Johnson on the TV series Twin Peaks. Amick's character endured terrible abuse at the hands of her husband, Leo, and was one of the most popular characters, ensuring her return in the feature film Twin Peaks: Fire Walk with Me. In 1992, Amick appeared in the Stephen King horror movie Sleepwalkers. She has also appeared in TV movies such as Love, Cheat and Steal (1993). A highlight of Amick's film career is the 1994 feature film Dream Lover, a thriller in which she co-starred with James Spader. Amick also appeared in the romantic comedy French Exit (1995) and the sci-fi thriller Bombshell (1996).

Amick's return to network TV came in the fall of 1995 with the much-publicized CBS dramatic series Central Park West. In 1998, Amick starred in the updated edition of Fantasy Island. Both shows only lasted one season.

After a decade of roles that failed to ignite the publicity Twin Peaks had, Amick gradually became a noticeable face in television with recurring roles on Gilmore Girls (2002 - 2003), ER (2004 - 2005), Jake in Progress (2005) and Joey (2004). In 2006, Amick was a regular in the sitcom Freddie which was subsequently cancelled. Amick guest starred in a number of episodes of the serial thriller Kidnapped on NBC, playing a strange and deadly assassin. She also had a recurring role in the second series of Dawson's Creek as the lead character's substitute film studies teacher. She most recently had a lead role in the short-lived CBS musical series Viva Laughlin. She had a recurring role in season 2 of Gossip Girl as Nate Archibald's "cougar" love interest, and she also appears in the second season of the Showtime series Californication. In 2008, Amick appeared as Christian Slater's wife on the NBC series My Own Worst Enemy.

• "My Own Worst Enemy" .... Angelica 'Angie' Spivey (9 episodes, 2008)
       - Henry and the Terrible... Day (2008) TV episode .... Angelica 'Angie' Spivey
       - Love in All the Wrong Places (2008) TV episode .... Angelica 'Angie' Spivey
       - Down Rio Way (2008) TV episode .... Angelica 'Angie' Spivey
       - High Crimes and Turducken (2008) TV episode .... Angelica 'Angie' Spivey
       - The Night Train to Moscow (2008) TV episode .... Angelica 'Angie' Spivey
        (4 more)
• "Californication" .... Janie Jones (5 episodes, 2008)
       - Blues from Laurel Canyon (2008) TV episode .... Janie Jones
       - La Ronde (2008) TV episode .... Janie Jones
       - Going Down and Out in Beverly Hills (2008) TV episode .... Janie Jones
       - In a Lonely Place (2008) TV episode .... Janie Jones
       - Coke Dick & First Kick (2008) TV episode .... Janie Jones
• "Gossip Girl" .... Duchess Catherine Beaton (4 episodes, 2008)
       - The Ex-Files (2008) TV episode (as Madchen Amick) .... Duchess Catherine Beaton
       - The Dark Night (2008) TV episode (as Madchen Amick) .... Duchess Catherine Beaton
       - Never Been Marcused (2008) TV episode (as Madchen Amick) .... Duchess Catherine Beaton
       - Summer Kind of Wonderful (2008) TV episode (as Madchen Amick) .... Duchess Catherine Beaton
• The Verdict (2008) (TV) .... Christine
• "Shark" .... Gina Romero (1 episode, 2008)
       - One Hit Wonder (2008) TV episode .... Gina Romero
• "Viva Laughlin" .... Natalie Holden (3 episodes, 2007)
       - What a Whale Wants (2007) TV episode .... Natalie Holden
       - Pilot (2007) TV episode .... Natalie Holden
       - Fighter (2007) TV episode .... Natalie Holden
• "Kidnapped" .... Yvonne Guttman / ... (3 episodes, 2006-2007)
       - Impasse (2007) TV episode .... Yvonne Guttman
       - Gone Fishing (2007) TV episode .... Yvonne Guttman
       - Burn, Baby, Burn (2006) TV episode .... Yvonne Guttman - Dragon Lady
• "Law & Order" .... Alissa Goodwyn (1 episode, 2006)
  ... aka Law & Order Prime (USA: informal title)
       - Home Sweet (2006) TV episode (as Madchen Amick) .... Alissa Goodwyn
• "Freddie" .... Allison (22 episodes, 2005-2006)