Moriarty made her film debut in Martin Scorsese's Raging Bull (1980), as Vikki LaMotta, wife of Jake (Robert De Niro). She was nominated for the Academy Award for Best Supporting Actress. Later, Moriarty played John Belushi's destructive, sultry neighbor in Neighbors, a film adaptation of Thomas Berger's novel of the same name. In 1982, she was severely injured in an automobile accident and required back surgery.

In 1985, Moriarty agreed to co-star with Jack Nicholson in The Two Jakes. However, after one day of shooting its production halted. Although the film was eventually released in 1990, Moriarty was no longer connected with the production. Moriarty returned to acting in 1987. Her first role since Neighbors was in the British thriller film White of the Eye, in which Moriarty played the wife of David Keith's character. Two years later, she appeared in the CBS series Wiseguy episode "Reunion".

In 1981, Moriarty married theatrical manager Carmine D'Anna and moved into a home in Malibu, California. On April 2, 1992, it was reported that Moriarty and D'Anna were divorcing and D'Anna sought $1 million under California's community property laws.

Moriarty began the decade with roles in the thriller film Burndown, Arnold Schwarzenegger's Kindergarten Cop and the soap opera parody Soapdish. She also appeared in the musical drama The Mambo Kings and the horror anthology TV series Tales from the Crypt, where Moriarty's performance earned her a Best Actress in a Dramatic Series CableACE Award. Her last performance of the year was a hard-as-nails prostitute in the screwball comedy film, The Gun in Betty Lou's Handbag. In 1993, Moriarty starred as John Goodman's wisecracking girlfriend and a film goddess in Joe Dante's period comedy Matinee, and had supporting roles in the comedies Another Stakeout (the sequel of 1987's Stakeout) and Me and the Kid. The following year, she guest-starred as half of the husband-wife con team in Universal Television's made-for-TV film Another Midnight Run. The actress' next role was the flirty barfly in Peter Medak's adventure film, Pontiac Moon (1994).

Moriarty played Debra Winger's friend in the romantic comedy Forget Paris (1995), followed by the vindictive Carrigan Crittenden in the live action film Casper. Shortly afterwards she starred with Andrew Dice Clay in the CBS series Bless This House, which was cancelled after 16 episodes during the 1996 season. That year Moriarty also played Hedy Burress's mother in Foxfire, the film adaptation of Joyce Carol Oates' novel. The next year, she played the alcoholic mother of a successful boxer in Opposite Corners; the mother of two sons (one a police officer and the other a crack addict) in A Brother's Kiss; a former exotic Dancer and Brad Hunt's aunt in Dream with the Fishes; Evan Rachel Wood's seriously-ill, alcoholic mother in Digging to China; Michael Rapaport's aunt in Cop Land and Alyssa Milano's mother in Hugo Pool.

On August 28, 1999, Moriarty and financier Joseph Gentile married on Long Island. She gave birth to twins Catherine Patricia and Joseph John on September 11, 2000, and on November 15, 2001, the couple's third child, Annabella Rose, was born.

Moriarty voiced characters in the animated TV series Stories from My Childhood episodes "The Golden Rooster" and "The Wild Swans" and the animated series Recess episode "Kids in the Mist". Other appearances included Hilary Duff's witch aunt in the direct-to-video film, Casper Meets Wendy; Randy Quaid's wife in the direct-to-video film, P.U.N.K.S., and Sharon Stone's friend in Gloria (a 1999 remake of the 1980 film written and directed by John Cassavetes). Roles followed in Crazy in Alabama, a film adaptation of Mark Childress's 1993 novel of the same name; New Waterford Girl, a Canadian comedy-drama, and the satirical film But I'm a Cheerleader. Moriarty played an FBI agent in Red Team, an abusive adoptive mother in the family film Prince of Central Park and a woman who fears death in the short film Next Stop, Eternity. Other roles included a widow suspected of killing her husband in an episode of Law & Order, crime boss Patti LoPresti in the Mafia comedy film (and sequel to 1999's Analyze This) Analyze That and a controlling mother in an episode of Law & Order: Special Victims Unit. In 2010, Moriarty played a bookie who sends two thugs to kill the main characters (Jennifer Aniston and Gerard Butler) in the romantic-action-comedy film The Bounty Hunter. On July 18, 2010, the Long Island International Film Expo honored the Actress with its Long Island Creative Achievement Award. Shortly afterwards, she guest-starred as Annalisa Gentili on an episode of Law & Order: Criminal Intent. The next year, Moriarty appeared as a nurse in the film 1320. In 2013 she played Armand Assante's wife in Once Upon a Time in Brooklyn and a sarcastic waitress in a black comedy, The Double. She returned to Law & Order: Special Victims Unit as Lieutenant Toni Howard for two episodes: season 14's "Poisoned Motive" and season 15's "Amaro's One-Eighty".