Despite her scene playing Eric Stoltz's wife being deleted from Grace of my Heart, Ryan made her 1999 movie debut in Roberta. She then appeared in You Can Count on Me and Keane. Albert Brooks chose her to play his wife in Looking for Comedy in the Muslim World in 2005, and 2007 brought both Dan in Real Life and Before the Devil Knows You're Dead. Her role as a star-struck sheriff's wife in Capote earned her positive reviews, but it was playing a hardened Welfare mom in Ben Affleck's Gone Baby Gone that finally brought her national attention.
After being voted Best Supporting Actress for Gone Baby Gone by the National Board of Review as well as the critics circles in New York, Los Angeles, Boston, San Francisco and Washington, DC, Ryan's performance was also nominated for a Golden Globe Award, a Screen Actors Guild Award and an Oscar for Best Performance by an Actress in a Supporting Role at the 80th Academy Awards
Ryan's current film Changeling, directed by Clint Eastwood, premiered in the fall of 2008, and she will also appear opposite Matt Damon in Paul Greengrass's next project, Green Zone.