DeCastro attended Stanford University in Stanford, California, where he was a member of the Stanford Cardinal football team from 2008 to 2011. He did not play in any games as a freshman in 2008. As a redshirt freshman in 2009 he started all 13 games at right guard. He was an honorable mention All-Pac-10 selection and a first team freshman All-American by College Football News. As a sophomore in 2010 he started all 13 games and was a first-team All-Pac-10 selection. Following his junior season in 2011, he was again a first-team Pac-12 selection, and was recognized as a unanimous first-team All-American. Afterward he decided to forgo his final season of college eligibility and enter the NFL Draft.
In October 2011, Sports Illustrated′s Tony Pauline ranked him as the No. 17 prospect on his midseason draft board. As the season progressed, he solidified that status as a first-round draft pick, being projected anywhere from No. 11 to No. 24 in pre-combine mock drafts. In a decent performance at the NFL Combine, DeCastro impressed scouts with "excellent movement skills." Still considered the top guard prospect available in the draft, he drew comparisons to Steve Hutchinson.
The Pittsburgh Steelers chose DeCastro with the 24th pick in the 2012 NFL Draft. He was the first offensive guard taken in the first round by the Steelers since Kendall Simmons in 2002. In the third preseason game against the Buffalo Bills, DeCastro injured both his right ACL and MCL. After DeCastro was carted off the field, Steelers head coach Mike Tomlin stated that the injury was a "potentially severe" right knee injury. While engaged with Bills defensive tackle, Marcell Dareus, DeCastro's teammate, offensive tackle Marcus Gilbert, fell on his right leg thus causing the injury. On November 26, DeCastro was activated to the active roster, while Gilbert was placed on injured reserve.