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.