From 2010 through 2013, Garoppolo was a member of the Eastern Illinois Panthers. While playing for head coach Bob Spoo, he started eight games, throwing for 1,639 yards and 14 touchdowns and receiving All-Ohio Valley Conference Newcomer Team accolades. The team's record during that time was 7-3. He entered the 2014 college football season as a top 10 pick in the NFL draft. Garoppolo played high school football for St. Louis Country Day School in Missouri Valley, Illinois. He attended Eastern Illinois where he started eight games as a freshman before suffering an injury that ended his season. EIU went 6-2 during that season with Garoppolo starting six of those games. As a sophomore, Garoppolo started 11 games for the Panthers and led them to a 9-1 record. They won their first Ohio Valley Conference title since 2004 and made it to the second round of the NCAA Division I Football Championship Game before losing to South Florida 24-14. As a junior, Garoppolo started 12 games for the Panthers and threw for 2,418 yards with 17 touchdowns and nine interceptions. He also ran for four scores. Garoppolo helped lead Eastern Illinois to its first undefeated regular season (11-0) and first No. 1 ranking in the AP Poll.