Castonzo grew up in Hawthorn Woods, Illinois where his parents Shari and Bill family ran an Italian restaurant.

[1] Castonzo attended Fork Union Military Academy in Virginia, where he was a two-way tackle for the Blue Devils and also saw action at the tight end spot, playing for Coach John Shuman.

[3] Becoming the first true freshman to start on the Boston College offensive line since Paul Zukauskas in 1998, Castonzo helped hold opponents to only 61 tackles-for-loss (fifth in the nation) and 22 quarterback sacks in 2007.

By protecting quarterback Matt Ryan at right tackle, he helped pave the way for the Eagles' 5,924 yards in total offense.

He set the record for career starts with 54 straight at Boston College and was a Rhodes Scholar nominee in 2010.

Head coach Jim Caldwell named him the starting left tackle to begin the regular season.

[12] He made his first career start and professional regular season debut in the Indianapolis Colts' season-opening 34–7 loss at the Houston Texans.

He started 16 regular season games and helped the Colts achieve an 11–5 record in their first year under Chuck Pagano and interim head coach Bruce Arians.

[14] Castonzo returned in 2013 and started 16 consecutive games to help the Colts finish first in the AFC South with an 11–5 record.

[14] On April 28, 2014, the Indianapolis Colts opted to exercise the fifth-year, $7.438 million option on Castonzo's rookie contract.

[17] In Week 11, Castonzo recorded his first career reception and touchdown, catching a one-yard pass from Andrew Luck.

Castonzo received the 12th highest grade among 84 qualifying offensive tackles from Pro Football Focus in 2015.