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After studying theatre at Boston University, she began acting in television. From 1985 to 1988, she was a regular in the soap opera As the World Turns, earning a Daytime Emmy Award. Moore made her breakthrough with Robert Altman's ensemble film Short Cuts (1993), followed by a critically acclaimed performance in Todd Haynes' Safe (1995). Starring roles in the blockbusters Nine Months (1995) and The Lost World: Jurassic Park (1997) established her as a Hollywood leading lady. She received Oscar nominations for her roles in the period films Boogie Nights (1997), The End of the Affair (1999), Far from Heaven (2002) and The Hours (2002); in the first of these, she played a 1970s pornographic actress, while in the other three, she starred as an unhappy mid-20th century housewife.

Her career progressed with roles in The Big Lebowski (1998), Magnolia (1999), Hannibal (2001), Children of Men (2006), A Single Man (2009), The Kids Are All Right (2010), Crazy, Stupid, Love (2011), and Maps to the Stars (2014). She won a Primetime Emmy Award for portraying Sarah Palin in the HBO film Game Change (2012) and the Academy Award for Best Actress for portraying an Alzheimer's patient in Still Alice (2014). Her highest-grossing releases came with the final two films in The Hunger Games film series (2014–2015) and the spy film Kingsman: The Golden Circle (2017). She has since starred in independent films and streaming projects, including Haynes' May December (2023) drama and the historical drama miniseries Mary & George (2024).

In addition to her acting work, she has written a series of children's books about Freckleface Strawberry. She is married to director Bart Freundlich, with whom she has two children.