Messina was married to Actress Rose Marie DeWitt from 1995 to 2006. Messina and Producer Jennifer Todd have two sons, Milo and Giovanni, born in 2008 and 2009, respectively. Messina is a Democrat.
He starred in an HBO pilot Anatomy of Hope, directed by J. J. Abrams. Simon Callow also starred, but the pilot was not picked up to series. In October 2007, Daily Variety named him as one of ten actors to watch. He starred in Devil, under the direction of John Erick Dowdle and Drew Dowdle, for Producer M. Night Shyamalan and Universal Pictures. In April 2010, Monogamy, directed by Dana Adam Shapiro and starring Messina and Rashida Jones, premiered at the Tribeca Film Festival, where the film won the jury prize for Best New York Narrative.
In 2014, Messina played the role of a cheating spouse in the music video for Sam Smith's "I'm Not the Only One". That same year, he directed the independent drama, Alex of Venice, starring Mary Elizabeth Winstead, Don Johnson and Matthew Del Negro.
He co-starred in friend Ben Affleck's crime drama Live by Night, which was released in December 2016.
