In Hollywood, she had her first roles playing teens with troubles. A few years later she started to act in mature roles. Besides films, Arquette appeared from the beginning of her career in television films. In 1982, she earned an Emmy Award nomination for the TV film The Executioner's Song. Thereafter, she played in many cinema movies and TV films and has worked with many of the most acclaimed film directors of the last twenty years. Arquette's first starring role was in John Sayles's Baby It's You, a highly regarded but little seen film. She starred in Desperately Seeking Susan alongside pop singer Madonna. After Hours also played to her comedic talents but failed to find an audience while 8 Million Ways to Die was buried by the studio. For a time, she quit Hollywood to work in Europe.

In 1989, Martin Scorsese offered her a part in New York Stories. Since then, Arquette has appeared, with few exceptions, in one or in several movies each year, some of them of notable interest, like Pulp Fiction and the David Cronenberg film, Crash. An offbeat choice, however, was to fly downunder and make the Australian film Wendy Cracked a Walnut (1990) (also known as "…Almost"). An expensive film, and a huge box office flop, only the musical score by Bruce Smeaton was generally noted by critics, for its musical innovation. In 1990, Arquette appeared on the cover and in a nude pictorial in Playboy's September issue, although she claimed it was without her prior knowledge or approval. In recent years, Arquette has also been expanding into directing. Recent films which she has directed include the documentaries Searching for Debra Winger (2002) and All We Are Saying (2005); she also produced both projects. Arquette also appeared in the short running What About Brian as Nicole Varsi. She also has appeared on Showtime's The L Word as Cherie Jaffe.

More recently, Arquette has focused her energies on spending time with her daughter and promoting awareness of breast cancer, while continuing with her work, now also as a director. Her mother had died of breast cancer in 1997. In 2002 her critically acclaimed documentary Searching for Debra Winger was released. In the film, Arquette interviews prominent and respected actresses (mostly between the ages of 30 and 60) in an attempt to find out whether it was practical for a working actress to successfully maintain a family.

• Way of the Warrior (2009) (pre-production) (rumored)
• Hectic (2009) (pre-production) (rumored) .... Sheila
• Convincing Clooney (2009) (filming) .... JC
• Exodus Fall (2009) (post-production) .... Marilyn Minor
• Inhale (2009) (post-production) .... Dr. Rubin
  
• "Lipstick Jungle" .... Tina Atwood (1 episode, 2008)
       - Chapter Fourteen: Let the Games Begin (2008) TV episode .... Tina Atwood
• Growing Op (2008) .... Diana
• Ball Don't Lie (2008) .... Francine
• "Medium" .... Michelle Todd (1 episode, 2008)
       - Lady Killer (2008) TV episode .... Michelle Todd
• "Dirt" .... Mia (1 episode, 2008)
       - And the Winner Is (2008) TV episode .... Mia
• Terra (2007) (voice)
• "What About Brian" .... Nicole Varzi / ... (24 episodes, 2006-2007)
       - What About Calling All Friends... (2007) TV episode .... Nicole Varzi
       - What About Secret Lovers... (2007) TV episode .... Nicole Varzi
       - What About All That Glitters... (2007) TV episode .... Nicole Varzi
       - What About Strange Bedfellows... (2007) TV episode .... Nicole Varzi
       - What About Temptations... (2007) TV episode .... Nicole Varzi
        (19 more)
• "The L Word" .... Cherie Jaffe (5 episodes, 2004-2007)
       - Legend in the Making (2007) TV episode .... Cherie Jaffe
       - Lifeline (2006) TV episode .... Cherie Jaffe
       - Limb from Limb (2004) TV episode .... Cherie Jaffe
       - Liberally (2004) TV episode .... Cherie Jaffe
       - Luck, Next Time (2004) TV episode .... Cherie Jaffe
• I-See-You.Com (2006) .... Lydia Ann Layton
• "Grey's Anatomy" .... Constance Ferguson (1 episode, 2005)
       - Owner of a Lonely Heart (2005) TV episode .... Constance Ferguson