She appeared in two other high-profile movies, Surviving Picasso (1996), starring Anthony Hopkins, and The Lost World: Jurassic Park (1997), directed by Steven Spielberg, before earning raves—and an Academy Award nomination for Best Supporting Actress—for her role as a motherly porn star and cocaine addict in Boogie Nights, written and directed by Paul Thomas Anderson and co-starring Mark Wahlberg and Burt Reynolds. She followed up on her Boogie Nights success with memorable roles in the Coen Brothers' The Big Lebowski (1998), starring Jeff Bridges, and the much-criticized 1998 shot-by-shot remake of Psycho, directed by Gus Van Sant. Moore had an incredible year in 1999, appearing in five major features and earning an Academy Award nomination for Best Actress for her starring turn in the film adaptation of Graham Greene’s novel, The End of the Affair, directed by Neil Jordan and co-starring Ralph Fiennes. She also starred in An Ideal Husband, based on the Oscar Wilde play and turned in impressive supporting turns in Altman’s Cookie’s Fortune, A Map of the World, co-starring Sigourney Weaver, and Anderson’s sprawling ensemble film, Magnolia. In 2000, she is reportedly slated to step into Jodie Foster's formidable shoes in Hannibal, the sequel to the chilling 1991 hit The Silence of the Lambs, co-starring Hopkins, who returns as the murderous Hannibal Lecter.

Moore has one son, Caleb, with the screenwriter and director Bart Freundlich, whom she met while filming The Myth of Fingerprints in 1997. The couple lives in New York City. Moore was previously married (from 1984 to 1995), to the actor John Gould Rubin.