Angarano was born in Brooklyn, New York, to Michael and Doreen Angarano; he has two sisters and a younger brother. He is of Italian descent.
His family owns and operates the dance studio Reflections in Dance in Canoga Park, California. Angarano graduated from Crespi Carmelite High School.
In the late 1990s, Angarano was one of the finalists for the role of young Anakin Skywalker in Star Wars: Episode I – The Phantom Menace, but lost to Jake Lloyd.
Angarano played the 11-year-old version of William Miller in Cameron Crowe's semi-autobiographical film Almost Famous in 2000.
In 2000, 12-year-old Angarano acted in Cover Me: Based on the True Life of an FBI Family. The following year, he landed his first major film role in Little Secrets, opposite Evan Rachel Wood and David Gallagher. Three years later, he starred in the Nickelodeon TV-movie Maniac Magee. He played the lead role in 2005's Sky High. Other film roles include parts in The Bondage, Black Irish, Man in the Chair, Snow Angels, The Final Season, One Last Thing..., The Forbidden Kingdom, Ceremony, The Brass Teapot and Red State.
On television, from 2001 to 2006, he had a recurring role on Will & Grace as Elliott, the son of Jack McFarland, a role he reprised in an episode of the show's 2017 reboot. In 2007, he appeared in four episodes of the show 24 as Scott Wallace, a teenager taken hostage by a terrorist. From 2014 to 2015, he played Dr. Bertram "Bertie" Chickering, Jr. on Cinemax's period drama The Knick. Currently, Angarano plays Eddie Zeidel on the Showtime series I'm Dying Up Here.