From 1985 until 1988, she was best-known for her role as ... Franny Hughes on As the World Turns. The part, which on occasion required her to play twins, won Moore a 1988 Daytime Emmy Award. The actress made her entrance into the big-screen arena with a 1990 debut in the schlocktastic Tales From the Darkside: The Movie (which also featured Steve Buscemi). Two years later, after making various TV movies, Moore reappeared in feature films with supporting parts in Curtis Hanson's tale of a babysitter gone bad, The Hand That Rocks the Cradle, and the comedy The Gun in Betty Lou's Handbag.

The following year, her exposure increased further thanks to roles in four different films that ranged from the half-baked thriller Body of Evidence to the sweetly quirky Benny and Joon to the big-budget smash The Fugitive to Robert Altman's epic Short Cuts. The last film gave Moore literal exposure in addition to the more figurative kind: she was required to play one scene naked from the waist down, something that predictably won the attention of critics and filmgoers. The intermittent praise that had been afforded Moore was amplified in 1994 with her performance as Yelena in Vanya on 42nd Street. The object of adjectives ranging from "luminescent" to "radiant" to "revelatory," the actress went on to play a very different character in Todd Haynes' Safe (1995). Moore won an Independent Spirit Award nomination for her portrayal of a woman (literally) sickened by the environment around her and further proved that she was an actress of distinct versatility. The same year she again demonstrated this ability with a starring role opposite Hugh Grant in the comedy Nine Months. Following a turn as one of Picasso's numerous lovers in Surviving Picasso (1996), a lead in the family drama The Myth of Fingerprints (she would later have a son with the film's director, Bart Freundlich), and a substantial part in The Lost World: Jurassic Park, Moore nabbed what was one of the plum roles of her career in Paul Thomas Anderson's Boogie Nights. For her portrayal of a porn actress, she won Golden Globe and Academy Award nominations.

A substantial role as an erotic artist in Ethan Coen's and Joel Coen's The Big Lebowski followed in 1998, along with a turn as Marion Crane's sister in Gus Van Sant's Psycho remake. The next year, Moore starred in a number of high-profile projects, beginning with Robert Altman's Cookie's Fortune, in which she was cast as the dim sister of a decidedly unhinged Glenn Close. A portrayal of the scheming Mrs. Cheveley followed in Oliver Parker's An Ideal Husband, with a number of critics asserting that Moore was the best part of the movie.

The actress then enjoyed another collaboration with director Anderson in Magnolia, an epic telling of nine interweaving stories inspired by Short Cuts and featuring an impressive cast that included Anderson regulars Philip Seymour Hoffman, Philip Baker Hall, and John C. Reilly. The same year, Moore also starred in the drama The End of the Affair, with Ralph Fiennes and Stephen Rea, and portrayed a grieving mother in A Map of the World, which premiered at the 1999 Toronto Film Festival. 2001 found the popular actress stepping into dark territory with the role of FBI Agent Clarice Starling in Ridley Scott's Hannibal, the long-awaited and eagerly anticipated follow-up to Jonathan Demme's numbingly suspenseful Silence of the Lambs.

A few short months later, Moore lightened the mood substantially with her humorous turn as a bumbling government scientist in the sci-fi comedy Evolution. Increasingly comfortable alternating between big-budget features and more personal art-house films, Moore bowled over audiences with a pair of powerhouse performances in both Far From Heaven and The Hours. A detailed throwback to the forgotten Hollywood melodrama, the former featured Moore's Oscar nominated role as a housewife who enters into a controversial relationship after discovering her husband's homosexuality and provided audiences a dose of Douglas Sirk that hadn't been tasted since the mid-1950s. A variation on the themes presented in Virginia Woolf's Mrs. Dalloway, the film version of Michael Cunningham's Pulitzer prize winning novel The Hours once again found Moore Oscar nominated for her role as a repressed 1950s era housewife, this time taking a special shine to Mrs. Dalloway while pondering an escape from her stifling marriage. In the wake of arguably her most successful year to date, Moore began to dabble behind the scenes for the first time, serving as executive producer on the 2003 independent adaptation of Wallace Shawn's play Marie and Bruce, a film that she also starred in. The following year, audiences could find Moore onscreen opposite Pierce Brosnan in the romantic comedy The Laws of Attraction and in the poorly-received thriller The Forgotten.

In 2005 she earned good reviews for The Prize Winner of Defiance, OH, but the film failed to catch on with audiences. She continued to work steadily starring opposite Sam Jackson in the adaptation of Richard Price's Freedomland, and starring opposite Clive Owen in Alfonso Cuaron's futuristic thriller Children of Men. She once again teamed with her director husband Bart Freundlich in the relationship comedy Trust the Man.