Moore the daughter of the late Anne Love, a psychiatric social worker who emigrated from Greenock, Scotland, and Peter Moore Smith, a military lawyer, judge, helicopter pilot, and army colonel. She has a younger sister, Valerie, and younger brother, novelist Peter Moore Smith III. Growing up as an "army brat", she lived in several places across the United States and Germany. Moore attended J.E.B. Stuart High School in Falls Church, Virginia and Frankfurt American High School in Frankfurt, Germany, graduating in 1979. She received her bachelor's degree at the College of Fine Arts at Boston University.
Moore moved to New York City in 1983, working as a waitress and performing in bit parts before being cast in the dual roles of Frannie Hughes and Sabrina Hughes on the soap opera As the World Turns, for which she won a Daytime Emmy Award.
Moore began starring in feature films in the early 1990s, mostly appearing in supporting roles. Her part in 1993's Short Cuts gained her critical acclaim and recognition, and she was cast in several high-profile Hollywood films, including 1995's romantic comedy Nine Months, and 1997's summer blockbuster The Lost World: Jurassic Park. Her first role as the central lead, Carol White, in the well-reviewed independent film Safe also attracted critical attention.
During the late 1990s and early 2000s, Moore appeared in a series of films that received Oscar recognition, including her roles in Boogie Nights (Best Supporting Actress nomination), The End of the Affair (Best Actress nomination), and her two 2002 films, The Hours (Best Supporting Actress nomination) and Far from Heaven (Best Actress nomination), for which she also won "Best Actress" from numerous critics groups and from the Venice Film Festival.
Moore was married to John Gould Rubin from 1986 to 1995. In 1996 she began a relationship with director Bart Freundlich, whom she wed on August 23, 2003. The couple had two children prior to their marriage: a son, Caleb (b. December 4, 1997), and a daughter, Liv Helen (b. April 11, 2002). She lives with her family in the West Village neighborhood of Manhattan.