Arquette was born Robert Arquette in Los Angeles, California, to Mardi Olivia (née Nowak), an actress, poet, theater operator, activist, acting teacher and therapist, and Lewis Arquette, an actor and director. Arquette's paternal grandfather was comedian Cliff Arquette. Arquette's mother was Jewish, the daughter of a Holocaust refugee from Poland, and Arquette's father was a convert to Islam and a descendant of explorer Meriwether Lewis. Arquette's siblings are actors Patricia, Rosanna, Richmond and David Arquette. Arquette is also Courteney Cox's sister-in-law, as Cox is married to Alexis' brother David.
Her first job in 1982 at age 12, was in the music video "She's a Beauty" for the San Francisco-based rock band The Tubes, cast as a young boy, "this little kid who's on a ride with all these women and whatnot."
At 22, Arquette landed her first significant acting role, playing a transgender character in Last Exit to Brooklyn. Sixteen years later, she went through her own transition from male to female, an experience that was documented in the film, Alexis Arquette: She's My Brother, which debuted at the 2007 Tribeca Film Festival.
Lesser known than her siblings, the majority of her film work has been limited to low-budget or independent films. These have included her critically acclaimed debut performance as male-to-female transsexual Georgette in Last Exit to Brooklyn. She also appeared in I Think I Do, Children of the Corn V: Fields of Terror, and Killer Drag Queens on Dope, among 40 other independent pictures.
Arquette has appeared in supporting roles in mainstream films, including Pulp Fiction, Threesome, Bride of Chucky and a memorable appearance as a Boy George fanatic in The Wedding Singer, singing "Do You Really Want to Hurt Me?" over and over. In 2001, Arquette played the Roman emperor Caligula in two episodes of the cult television show Xena: Warrior Princess. Also in 2001, Arquette guest starred in the Friends episode The One with Chandler's Dad as a waiter in drag, in the show's 7th season. In September 2005, VH1 announced her casting in an upcoming season of the reality show The Surreal Life.
On January 31, 2007, Arquette was a featured celebrity client and guest judge on the premiere episode of Bravo Channel's television show Top Design, where she was described by one of the contestants as "Iggy Pop in drag". Arquette also made a cameo appearance in Robbie Williams' "She's Madonna" video. On February 26, 2007, Arquette was promoting the DVD Release of Killer Drag Queens on Dope  on The Adam Carolla Show. Danny Bonaduce, a co-host, asked Arquette if she had a penis. The question, and her refusal to answer sparked an argument between Carolla, Bonaduce, and Arquette, ending in Arquette storming out of the studio and violently pushing sound equipment at them as she was leaving.
- Last Exit to Brooklyn (1989)
- Death of a Schoolboy (1990)
- Miracle Beach (1992)
- Jumpin' at the Boneyard (1992)
- Terminal Bliss (1992)
- Of Mice and Men (1992)
- The Killing Box (1993)
- Grief (1993)
- Jack Be Nimble (1993)
- Frank and Jesse (1994)
- Threesome (1994)
- Pulp Fiction (1994)
- Don't Do It (1994)
- Paradise Framed (1995)
- Wigstock: The Movie (1995)
- Frisk (1995)
- White Man's Burden (1995)
- Kiss & Tell (1996)
- Sometimes They Come Back... Again (1996)
- Things I Never Told You (1996)
- Never Met Picasso (1996)
- Scream, Teen, Scream (1996)
- Inside Out (1997)
- I Think I Do (1997)
- Goodbye America (1997)
- Close To (1997)
- Love Kills (1998)
- Fool's Gold (1998)
- The Wedding Singer (1998)
- Cleopatra's Second Husband (1998)
- Children of the Corn V: Fields of Terror (1998)
- Bride of Chucky (1998)
- Tomorrow by Midnight (1999)
- Out in Fifty (1999)
- She's All That (1999)
- Clubland (1999)
- Citizens of Perpetual Indulgence (2000)
- Piccadilly Pickups (2000)
- The Price of Air (2000)
- Boys Life 3 (2000)
- The Woman Every Man Wants (2001)
- Xena: Warrior Princess (2001)
- Audit (2001)
- Digital Sex (2001)
- The Trip (2002)
- Spun (2002)
- The Movie Hero (2003)
- Wasabi Tuna (2003)
- Killer Drag Queens On Dope (2003)
- Lords of Dogtown (2005)
- Hubert Selby Jr: It'll Be Better Tomorrow (2005)
- Alexis Arquette: She's My Brother (2007)
- Rosanna Arquette Biography (1959-)
- Pfefferman, Naomi. "Arquette Reconnects", The Jewish Journal of Greater Los Angeles, 2002-10-08. Retrieved on 2006-12-13.
- Vallance, Tom. "Obituary: Lewis Arquette", The Independent, 2001-02-16. Retrieved on 2006-12-13.
- Patricia Arquette - Cranky Critic StarTalk - Movie Star Interviews
- USA WEEKEND Magazine
- Patricia Arquette: The not-so-dippy hippie - Features, Film & TV - Independent.co.uk
- Chris Lee (1998). Interview with Alexis Arquette. indexmagazine. Retrieved on 2007-04-05.
- Lorraine Ali". None of Us Are Safe" Newsweek, May 13, 2007.
- Killer Drag Queen on Dope
- The Official Adam Carolla Show Blog (2007-02-26). Archived from the original on 2012-06-29. Retrieved on 2007-04-09.