She made her feature film debut in Ang Lee's The Ice Storm in 1997. Subsequent film roles include: Go, Teaching Mrs. Tingle (both 1999), Wonder Boys, The Gift (both 2000), Abandon, Phone Booth (both 2002), The Singing Detective, Pieces of April (both 2003), Batman Begins, Thank You for Smoking (both 2005), Mad Money (2008), Don't Be Afraid of the Dark (2010), Jack and Jill (2011), Miss Meadows (2014), Woman in Gold, Touched with Fire (both 2015) and Logan Lucky (2017).
In 2008, she made her Broadway theatre debut in a production of Arthur Miller's All My Sons. In 2011, she played Jacqueline Kennedy in the TV miniseries The Kennedys, a role she reprised in The Kennedys: After Camelot (2017). She made her directorial debut with the 2016 film All We Had, in which she also starred.
Her marriage to actor Tom Cruise, which lasted from 2006 to 2012, led to a great deal of media attention, with the pair being called a supercouple and being given the nickname "TomKat" in various countries.