Laurinaitis attended Ohio State University, where he played for coach Jim Tressel's Ohio State Buckeyes football team from 2005 to 2008. As a true freshman in 2005, he played in all 12 games eventually reaching No. 2 on the depth chart at strong-side linebacker behind Bobby Carpenter. After Carpenter broke a leg on the first play from scrimmage in their rivalry game against Michigan, Laurinaitis played the rest of that game, and also started in their Fiesta Bowl victory over Notre Dame. At the end of the 2006 regular season, Laurinaitis led the team in tackles (115) and interceptions (5), and also had 8.5 tackles for loss and 4.0 sacks.
In 2006 Laurinaitis won the Nagurski Award as the nation's best defensive player, and was also named a finalist for the Butkus and Bednarik awards. He was a first-team All-Big Ten selection, and was recognized as a consensus first-team All-American. Laurinaitis won the Butkus Award for most outstanding college linebacker in 2007. He was also recognized as a unanimous first-team All-American in 2007, having been named to the first teams of multiple selectors including the Associated Press (AP), the American Football Coaches Association (AFCA), FWAA, Sporting News, the Walter Camp Foundation, and Rivals.com. He was honored as the Big Ten Defensive Player of the Year.
James is one of two children born to Joseph and Julie Laurinaitis. He has Lithuanian roots on his father's side. James has a half-brother, Joseph, Jr., from his father's first marriage, who is a veteran of the Iraq War and training to become a police officer. His younger sister, Jessica, played on her high school hockey team and graduated from high school in 2008.