Arquette had starring roles in several critically acclaimed films, including True Romance (1993), Ed Wood (1994), Flirting with Disaster (1996), Lost Highway (1997), The Hi-Lo Country (1998), Bringing Out the Dead (1999), and Holes (2003).

In 1987, Arquette's first starring roles included pregnant teenager Stacy in the television film Daddy,[24] boarding school student Zero in Pretty Smart, and Kristen Parker in A Nightmare on Elm Street 3: Dream Warriors, alongside Robert Englund as Freddy Krueger and Heather Langenkamp as Nancy Thompson.

She was asked to reprise her role in the sequel, A Nightmare on Elm Street 4: The Dream Master (1988), but she declined the offer in order to do other projects.

Her roles in the early 1990s were in low budget and independent films, including Prayer of the Rollerboys (1990) as love interest of Corey Haim's character, The Indian Runner (1991), which was the directorial debut of Sean Penn; and the drama Inside Monkey Zetterland.

In 1992, she won a CableACE Award for Best Lead Actress in a Mini-Series for her portrayal of a deaf girl with epilepsy in Wildflower, directed by Diane Keaton and also starring Reese Witherspoon.

In her early career, Arquette received the most recognition for her role as Alabama Whitman, a free-spirited, kind-hearted prostitute in Tony Scott's True Romance (1993).

The film was a moderate box office success but became a cultural landmark because of Quentin Tarantino's screenplay, which preceded Pulp Fiction, although some critics were deterred by the graphic violence.

In one scene, Arquette puts up a fierce physical struggle in a fight with James Gandolfini (as a viciously sadistic killer) which her character ultimately wins.

[27] Richard Corliss of Time Magazine made similar statements and also likened the film to the earlier, seminal Bonnie and Clyde.

[28] Arquette next appeared in the television film Betrayed by Love (1994), and the well-received biopic Ed Wood, directed by Tim Burton and starring Johnny Depp, where she portrayed his girlfriend.

[29] Although the film had lackluster reviews, Arquette's performance as an American tourist in Burma during the 8888 Uprising was regarded as one of the work's strong points.

Michael Sragow, writing for The New Yorker, stated "Arquette gives the kind of mighty physical performance usually delivered by men in existential action classics like "The Wages of Fear," but she suffuses it with something all her own - she's bulletproof yet vulnerable.

"[30] Hal Hinson of The Washington Post remarked that the film was "odd, brilliant in places, but frustrating all the same," commenting that "Arquette shows real grit when the chips are down".

[32] Flirting with Disaster grossed $14 million at the American box office and was screened in the Un Certain Regard section at the 1996 Cannes Film Festival.

[36] In 1997, Arquette starred in David Lynch's neo-noir psychological thriller Lost Highway, in dual roles as Renee Madison and Alice Wakefield.

Arquette played an elusive femme fatale in a critically revered performance that enabled her to draw on her sexuality more than any other previous role.

Roger Ebert, of the Chicago Sun-Times, disliked the film, saying there was "no sense to be made of it" and voiced his distaste over a scene in which Arquette's character is asked to disrobe at gunpoint.

Nightwatch was not a box office success and received poor reviews by critics, many of whom considered it an unnecessary, inferior retelling of the original film.

[43] Stephen Holden of The New York Times said, "In its best moments the movie feels like an epic hybrid of Red River and The Last Picture Show.

[45] Critics were not as receptive of the film as audiences, with Roger Ebert remarking "possibly the funniest movie ever made about Catholicism – from a theological point of view".

[47][48] The film united her with then-husband Nicolas Cage and received highly favourable critical reviews, but was a box office flop.

In 2003, she portrayed the controversial pornographic film star Linda Lovelace in the little known Deeper than Deep, which was followed with the more family orientated Disney produced Holes, as Kissin' Kate Barlow.

[54] After the humdrum reception of Tiptoes, Arquette did not appear in another film until 2006's Fast Food Nation, directed by Richard Linklater.

The film is brimming with grand ambitions but trips on many of them as some characters aren't given enough screen time to register and others vanish just when you want to learn more about them.

Critic Katie McDonahugh, writing for Salon, states "the role gave [Arquette] space to be all of these messy things at once, and her performance was a raw, gutsy meditation on those profoundly human contradictions".

[65] Margaret Pomeranz, writing for ABC Australia, called Arquette's performance "stunning" and praised the film, further remarking that "the elision from one time to another is subtle and seamless.

In early 2015, Arquette began starring in the CBS series CSI: Cyber, a show about FBI agents who combat Internet-based crimes.

For her performance, Arquette received the Primetime Emmy Award for Outstanding Supporting Actress in a Limited Series or Movie.

[83] In April 2010, she teamed up with welding students of the Robert Morgan Educational Center in Miami, Florida, to build shelters in Haiti from 20 used shipping containers, to provide housing to people displaced by the earthquake.