For his lead role as Miles Roby in the 2005 miniseries Empire Falls, Harris was nominated for the Primetime Emmy Award for Outstanding Lead Actor in a Miniseries or a Movie and the Golden Globe Award for Best Actor – Miniseries or Television Film.[16] He then appeared as a vengeful mobster in David Cronenberg's A History of Violence (2005). In 2006, he portrayed composer Ludwig van Beethoven in the film Copying Beethoven,[17] and starred in the television documentary film The Armenian Genocide as American diplomat Leslie Davis. He next appeared alongside Casey Affleck and Morgan Freeman in the Ben Affleck-directed neo-noir mystery film Gone Baby Gone (2007).[18] Harris then co-starred as the antagonist Mitch Wilkinson in National Treasure: Book of Secrets (2007), alongside Nicolas Cage.[19]
In 2010, he and wife Amy Madigan appeared together in Ash Adams' independent crime drama Once Fallen. Later that same year, Harris starred in the survival drama The Way Back as Mr. Smith. His performance received much critical praise, and he was suggested by critics to receive a fifth Oscar nomination.[20] In 2012, he co-starred alongside Sam Worthington in the thriller film Man on a Ledge for Summit Entertainment.[21] He then won the Golden Globe Award for Best Supporting Actor – Series, Miniseries or Television Film and was nominated for the Primetime Emmy Award for Outstanding Supporting Actor in a Miniseries or a Movie for his performance as Senator John McCain in the HBO made-for-television drama Game Change.[22] The following year, he appeared in the western thriller Sweetwater,[23] and starred opposite Annette Bening in the romantic drama film The Face of Love.[24] Harris then voiced Mission Control in Alfonso Cuarón's sci-fi epic Gravity (2013), starring Sandra Bullock and George Clooney.[25]
In 2015, he portrayed the title character in the crime tragedy film Cymbeline.[26] He will star in Alejandro González Iñárritu's upcoming Starz drama series The One Percent with Hilary Swank and Ed Helms.[27] Harris will portray the villain in HBO's upcoming sci-fi thriller television series Westworld.[28] In 2016, he will star on stage alongside Madigan and Taissa Farmiga in The New Group's production of Sam Shepard's play Buried Child.[29] That same year, Harris will co-star in James Franco's In Dubious Battle, based on the novel of the same name by John Steinbeck.[30] In 2017, he is set to appear in the Dean Devlin sci-fi film Geostorm, alongside Gerard Butler and Andy García.[31]