She rose to international prominence for playing Monica Geller in the NBC sitcom Friends (1994–2004) and Gale Weathers in the horror film franchise Scream (1996–present).

In 1993, Cox co-starred in the short-lived CBS sitcom The Trouble with Larry, alongside Bronson Pinchot and Perry King.

[24] In 1994, Cox was asked to audition for the starring role of Rachel Green on a new sitcom, Friends; she was cast as Monica Geller instead.

[25] At first the most famous cast member of the new show, Cox joined Jennifer Aniston (Rachel Green), Lisa Kudrow (Phoebe Buffay), Matt LeBlanc (Joey Tribbiani), Matthew Perry (Chandler Bing) and David Schwimmer (Ross Geller) for what became her most famous role, lasting for ten seasons until 2004.

[26][27] According to the Guinness Book of World Records (2005), Cox (along with her female co-stars) became the highest-paid TV actress of all time, with her US$1 million-per-episode fee for the final two seasons of Friends.

A joke reference to this is made in the opening credits of the episode "The One After Vegas", where the rest of the cast has "Arquette" added to their names.

[36] Cox also hosted an episode of the variety sketch series Saturday Night Live in July 1995,[37] and appeared in the crime thriller film The Runner (1999).

[41] She had a cameo appearance in the big-budget remake The Longest Yard (2005) as Lena, the girlfriend of Paul Crewe (Adam Sandler), and co-starred with Tim Allen in the critically derided Zoom (2006).

Cox starred as Lucy Spiller, a cynical tabloid editor, in the FX television drama series Dirt, which premiered in 2007.

[46] In July 2008, Entertainment Weekly announced that Cox signed on to star in a three-episode arc for the television medical comedy series Scrubs.

[49] Also in 2009, she began her role as the star of the single-camera ABC comedy series Cougar Town, playing a newly single 40-year-old mother on the hunt for new experiences.

[50][51][52] It is notably Cox's most successful work since Friends, earning her a nomination for the Golden Globe Award for Best Actress – Television Series Musical or Comedy.

[55][56] She made her directorial debut and had a cameo appearance in a Lifetime television drama film TalhotBlond, which premiered on the network on June 23, 2012.

[61] In 2016, Cox starred in the independent drama film Mothers and Daughters, alongside Susan Sarandon, Mira Sorvino, and Sharon Stone.

[62] In 2019, she created and executive produced the Facebook Watch documentary series 9 Months with Courteney Cox, which focuses on "people from across the country of various race, religion, and class as they self-document their 9-month journey of pregnancy".

Cox reprised her role as Gale Weathers for the fifth Scream film, which was directed by Matt Bettinelli-Olpin and Tyler Gillett.

[72][73] Also in 2022, she signed on to star alongside Greg Kinnear in the Starz horror comedy series Shining Vale, from creators Sharon Horgan and Jeff Astrof; she plays Patricia "Pat" Phelps, who moves her family "from the 'crazy' of the city to a large, old house in the suburbs where evil and humor collide.

[77][78] She is set to executive produce and star as Brittany Wagner in the Spectrum Originals adaptation of the documentary series Last Chance U.

[86] On October 11, 2010, Cox and Arquette announced that they had separated, although they still maintain a close friendship and ongoing business relationship in Coquette Productions.