At the urging of her brother's childhood friend, comedian Jon Lovitz, Kudrow began her comedic career as a member of The Groundlings, joining the ranks of those such as Will Ferrell and Janeane Garofalo. Briefly, Kudrow joined with Conan O'Brien and director Tim Hillman in the short-lived improv troupe Unexpected Company. She was also the only regular female member of the Transformers Comedy Troupe. She played a role in an episode of the NBC sitcom Cheers. She tried out for Saturday Night Live in 1990, but the show chose Julia Sweeney instead. She had a recurring role as Kathy Fleisher in three episodes of season one of the Bob Newhart sitcom Bob (CBS, 1992-1993). Prior to Friends, she appeared in at least two produced network pilots: NBC's Just Temporary (also known as Temporarily Yours) in 1989, playing Nicole; and CBS' Close Encounters (also known as Matchmaker) in 1990, playing a Valley girl. Kudrow was hired to play the role of Roz in Frasier, but the part was re-cast with Peri Gilpin during the filming of the pilot episode. Kudrow said in 2000 that when rehearsals started, "I knew it wasn't working. I could feel it all slipping away, and I was panicking, which only made things worse". However, one of the people working on Frasier also worked on Friends and suggested Kudrow audition for the show. Her first recurring television role was Ursula Buffay, the eccentric waitress on the NBC sitcom Mad About You. This character would later appear in Friends as Phoebe's twin sister.

The role of Ursula led to her ensemble starring role on the NBC sitcom Friends (1994 - 2004) as Phoebe Buffay, for which she won the 1998 Emmy Award for Outstanding Supporting Actress in a Comedy Series; she was the first Friends cast member to win an Emmy, as well as the most frequently nominated of the cast, receiving six nominations. The program was a long-running hit, and Kudrow and her fellow cast-members, gained wide renown among television viewers. According to the Guinness Book of World Records (2005), Kudrow and co-stars Jennifer Aniston and Courteney Cox became the highest paid TV actresses of all time, earning $1 million per episode for the tenth season of Friends. Her film credits include comedic roles in Romy and Michele's High School Reunion, Hanging Up, Marci X, Analyze This and its sequel Analyze That. However, Kudrow has also starred in dramatic roles including the biographical Wonderland about the late porn star John Holmes. She has garnered critical acclaim in dramatic roles for writer-director Don Roos in the films The Opposite of Sex and Happy Endings.

After Friends, Kudrow starred as protagonist Valerie Cherish on the single-season HBO series The Comeback (premiered June 5, 2005), about a has-been sitcom star trying for a comeback. She also served as co-creator, writer, and executive producer. Kudrow received an Emmy nomination for Outstanding Lead Actress in a Comedy Series for her work on The Comeback, making her the first Friends cast member to receive a major award nomination since Friends ended. She has been a vocal performer on episodes of animated television series, including as Aphrodite on Hercules: The Animated Series, and as Springfield Elementary School student Alexandra Whitney on The Simpsons She was the voice of the female grizzly bear Ava in the live action movie Dr. Dolittle 2. She has also appeared, alongside her niece, in a television commercial for Nintendo's Personal Trainer: Cooking.

• 17 Photos of Isabel (2009) (filming) .... Carolyne
• Paper Man (2009) (filming)
• Dirty Girl (2009) (post-production) .... Sue Ann
• Bandslam (2009) (completed) .... Karen Burton
  
• Hotel for Dogs (2009) .... Lois Scudder
• Powder Blue (2009)
• "Web Therapy" .... Dr. Fiona Wallice / ... (3 episodes, 2008)
       - An Old Flame: Part 1 (2008) TV episode .... Dr. Fiona Wallace
       - An Old Flame: Part 2 (2008) TV episode .... Dr. Fiona Wallice
       - An Old Flame: Part 3 (2008) TV episode .... Dr. Fiona Wallice
• P.S. I Love You (2007) .... Denise
• Kabluey (2007) .... Leslie
• "American Dad!" .... The Ghost of Christmas Past (1 episode, 2006)
       - The Best Christmas Story Never (2006) TV episode (voice) .... The Ghost of Christmas Past
• "Hopeless Pictures" .... Sandy (2 episodes, 2005)
       - Episode #1.4 (2005) TV episode (voice) .... Sandy
       - Episode #1.2 (2005) TV episode (voice) .... Sandy
• "The Comeback" .... Valerie Cherish (13 episodes, 2005)
       - Valerie Does Another Classic Leno (2005) TV episode .... Valerie Cherish
       - Valerie Shines Under Stress (2005) TV episode .... Valerie Cherish
       - Valerie Stands Out on the Red Carpet (2005) TV episode .... Valerie Cherish
       - Valerie Gets a Magazine Cover (2005) TV episode .... Valerie Cherish
       - Valerie Hangs with the Cool Kids (2005) TV episode .... Valerie Cherish
        (8 more)
• "Father of the Pride" .... Foo-Lin (2 episodes, 2004-2005)
       - The Siegfried and Roy Fantasy Experience Movie (2005) TV episode (voice) .... Foo-Lin
       - What's Black and White and Depressed All Over? (2004) TV episode (voice) .... Foo-Lin
• Happy Endings (2005) .... Mamie
• "Friends" .... Phoebe Buffay / ... (238 episodes, 1994-2004)
       - The Last One: Part 1 (2004) TV episode .... Phoebe Buffay-Hannigan
       - The Last One: Part 2 (2004) TV episode .... Phoebe Buffay-Hannigan
       - The One with All the Other Ones: Part 1 (2004) TV episode .... Phoebe Buffay / Herself
       - The One with All the Other Ones: Part 2 (2004) TV episode .... Phoebe Buffay / Herself
       - The One with Rachel's Going Away Party (2004) TV episode .... Phoebe Buffay-Hannigan
        (233 more)
• Wonderland (2003) .... Sharon Holmes
• Marci X (2003) .... Marci Feld