However, she was unhappy with the film's nude scene, remarking in an interview that the idea of the general public seeing her naked made her feel uncomfortable and exploited, and that most of the offers she had received since demanded that she similarly expose herself.

[12] Her first starring role was in John Sayles's film, Baby It's You (1983), highly regarded by Rotten Tomatoes reviewers[13] but not widely distributed.

Following the commercial and critical success of Lawrence Kasdan's Silverado (also 1985), the limited success of the Martin Scorsese film After Hours (also 1985) and the commercial flop 8 Million Ways to Die (1986), also a critical failure, she quit Hollywood to work in Europe, acting in Luc Besson's The Big Blue (1988).

In 2017, Arquette alleged (along with almost a hundred other women from the entertainment industry), that the then film producer Harvey Weinstein sexually harassed her, threatened her because of her refusal to enter his hotel room, and subsequently saw to it that she was paid less for Pulp Fiction, then no longer cast her in A-list lead roles because of her rejection of his quid pro quo sexual harassment proposition; Weinstein was convicted of sex offences in 2020.

When news broke about Weinstein's sexual offending in October 2017, Arquette was one of the first actresses to speak openly about his misconduct, with Ronan Farrow for The New Yorker and The New York Times's Jodi Kantor.

[16] In the documentary Untouchable (2019) about Weinstein focusing on those who accused him of sexual abuse, Arquette, Paz de la Huerta, and Erika Rosenbaum were among those interviewed.

In an August 8, 2019 interview with TheWrap, Arquette said the FBI advised her to make her Twitter account private after online critics complained about her tweeting that she had shame for being "white and privileged".

However, as a joke, the band members initially played along with the common assumption that the song was based on Arquette, who was dating Toto keyboard player Steve Porcaro at the time.

Arquette herself played along with the joke, commenting in an interview that the song was about "my showing up at 4 a.m., bringing them juice and beer at their sessions.

[21][22] Arquette's first three marriages—to director Tony Greco, film composer James Newton Howard, and restaurateur John Sidel—ended in divorce.