In 2006 he portrayed Christopher Columbus in Twentieth Century Fox's Night at the Museum. In 2008 he played General Glozelle, the leader of Miraz's Telmarine troops in The Chronicles of Narnia: Prince Caspian. He has worked with American director Ron Howard twice: in the 2009 film Angels & Demons, the adaptation of the novel of the same name by Dan Brown, in which he played the role of Inspector Ernesto Olivetti, and in the 2013 film Rush, in which he played the role of Formula One racing car driver Clay Regazzoni.
Favino has been in a realtionship with Italian actress Anna Ferzetti since 2003. The couple have two daughters together, one born in 2006 and the other born in 2012.