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McAdams made her Hollywood film debut in the comedy The Hot Chick in 2002. She rose to fame in 2004 with her portrayal of Regina George in the comedy Mean Girls and with the romantic drama The Notebook. In 2005, she starred in the romantic comedy Wedding Crashers, the psychological thriller Red Eye, and the comedy-drama The Family Stone. She was hailed by the media as Hollywood's new "it girl", and received a nomination for the BAFTA Rising Star Award.

After a hiatus, McAdams gained further prominence starring in the films The Time Traveler's Wife (2009), Sherlock Holmes (2009), Morning Glory (2010), Midnight in Paris (2011), The Vow (2012), and About Time (2013). For her portrayal of journalist Sacha Pfeiffer in the drama Spotlight (2015), she was nominated for the Academy Award for Best Supporting Actress. This was followed by roles in the Marvel Cinematic Universe films Doctor Strange (2016) and Doctor Strange in the Multiverse of Madness (2022), the romantic drama Disobedience (2017), the comedies Game Night (2018) and Eurovision Song Contest: The Story of Fire Saga (2020), the comedy-drama Are You There God? It's Me, Margaret. (2023), and the horror-thriller Send Help (2026).

On television, she starred in the second season of the HBO anthology crime drama series True Detective (2015), earning a Critics' Choice Television Award for Best Actress in a Miniseries or Movie nomination. She made her Broadway debut playing a struggling single mother in Amy Herzog's play Mary Jane (2024) for which she was nominated for a Tony Award for Best Actress in a Play.