At the urging of her brother’s childhood friend, comedian Jon Lovitz, she began her comedic career as a member of The Groundlings, an improv and sketch comedy school in Los Angeles. Kudrow has credited Cynthia Szigeti, her improv teacher at The Groundlings, for changing her perspective on acting, calling her “the best thing that happened, on so many levels.” 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), a role she played after taking part in the series finale of Newhart’s previous series Newhart. 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.

On May 27, 1995, Kudrow married French advertising executive Michel Stern. They have a son, Julian Murray Stern. Kudrow’s pregnancy was written into the fourth season of Friends with her character, Phoebe, having triplets as a surrogate mother for her younger half-brother Frank (Giovanni Ribisi) and his wife Alice (Debra Jo Rupp). In 2019, during an interview with Marc Maron, Kudrow revealed that she experienced body dysmorphic disorder while working on the show.

Kudrow has been honored with numerous accolades over her career. For her role in the sitcom Friends, she received six nominations at the Primetime Emmy Awards, winning in 1998 for Outstanding Supporting Actress in a Comedy Series. Kudrow has also received twelve nominations and two wins at the Screen Actors Guild Awards, as well as one win and eight nominations at the American Comedy Awards.

Kudrow was cast to play the role of Roz Doyle in Frasier, but the role was re-cast with Peri Gilpin during the taping 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.” Her first recurring television role was Ursula Buffay, the eccentric waitress on the NBC sitcom Mad About You. Kudrow would reprise the character on the NBC sitcom Friends, in which Kudrow co-starred as massage therapist Phoebe Buffay, Ursula’s twin sister.

Kudrow co-created an improvised comedy web series, Web Therapy on Lstudio.com. The improv series, which launched online in 2008, has earned several Webby nominations and one Outstanding Comedic Performance Webby for Kudrow, who plays therapist Fiona Wallice. She offers her patients three-minute sessions over iChat. In July 2011, a reformatted, half-hour version of the show premiered on Showtime, before being cancelled in 2015 after four seasons. Kudrow has guest starred on multiple television series such as Cougar Town, BoJack Horseman, Angie Tribeca, Unbreakable Kimmy Schmidt, and Scandal.

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. Nine years after the original season, HBO revived the series in 2014 for an abbreviated second season. Kudrow received two Emmy nominations for Outstanding Lead Actress in a Comedy Series for her work on The Comeback. Her production company is ‘Is or Isn’t Entertainment’.

Following Friends, Kudrow has also appeared in films such as Easy A, Hotel for Dogs (film), Happy Endings, and Neighbors. In 2016, she reprised her role as Carol Gladstone in Neighbors 2: Sorority Rising, and co-starred in the thriller film The Girl on the Train.

On April 8, 2020, it was announced that Kudrow was cast as Maggie Naird in the upcoming Netflix comedy series, Space Force.