As a senior in 2013, Garoppolo broke Tony Romo's school records for career passing touchdowns, career passing yards, and passing touchdowns in a season. That season, he also won the Walter Payton Award, which goes to the best offensive player in the Football Championship Subdivision (FCS).
Garoppolo was born and raised in Arlington Heights, Illinois and attended Rolling Meadows High School in Rolling Meadows, Illinois. He is from a "tight-knit, big Italian family,” and is the third of four sons born to Denise and Tony Garoppolo.
Garoppolo played football for the Eastern Illinois Panthers from 2010 to 2013. In his freshman year, he started eight games, passing for 1,639 yards and 14 touchdowns and earning All-Ohio Valley Conference Newcomer Team honors playing under head coach Bob Spoo. He went on to start every further game in his time at Eastern Illinois, passing for 2,644 yards and 20 touchdowns in 2011, 3,823 yards and 31 touchdowns in 2012, and 5,050 yards and 53 touchdowns in 2013, breaking the school record for career pass completions previously held by Dallas Cowboys quarterback Tony Romo.
In his senior season, Garoppolo won the Walter Payton Award, given to the most outstanding offensive player in the Division I Football Championship Subdivision under head coach Dino Babers with his uptempo no huddle offense. As a result of his successful senior season, he was named the 2013–14 OVC Male Athlete of the Year and the 2013 College Football Performance FCS National Quarterback of the Year.
Garoppolo was considered one of the better quarterback prospects for the 2014 NFL Draft.
The New England Patriots drafted Garoppolo in the second round of the 2014 NFL Draft, with the 62nd pick overall. Garoppolo was the first player from the Football Championship Subdivision drafted in 2014, and the highest-drafted quarterback New England had selected since Drew Bledsoe was picked first overall in 1993.
In 2014, Garoppolo made his regular season debut in the 4th quarter of the Patriots' Week 4 41–14 road loss to the Kansas City Chiefs on Monday Night Football. He led the Patriots on a scoring drive, which led to his first career passing touchdown on a 13-yard pass to tight end Rob Gronkowski on his first drive. He finished the night completing six of seven passes for 70 yards and one touchdown, with a passer rating of 147.9.
In his rookie season, Garoppolo played in 6 games. He completed 19 of 27 passes for 182 yards and a touchdown with a 101.2 passer rating and had 10 rushing attempts for 9 yards. While Garoppolo did not take any snaps in the New England Patriots' Super Bowl XLIX win, he was credited with helping to prepare the Patriots defense for Seattle Seahawks quarterback Russell Wilson.
In 2015, Garoppolo appeared in five games and completed 1 of 4 passes for 6 yards.
After starting quarterback Tom Brady was suspended by the league for four games for Deflategate, coach Bill Belichick named Garoppolo the starting quarterback for the first game of the 2016 season, and he was expected to stand in for Brady for all four games. Garoppolo completed 24 of 33 passes for 264 yards and a touchdown in a 23–21 Week 1 victory over the Arizona Cardinals. He threw for 234 yards and three touchdowns in Week 2 against the Miami Dolphins before being sidelined with a shoulder injury in the second quarter. He sprained his AC joint after a hit by Dolphins' linebacker Kiko Alonso that kept him out the next two games, giving the starting job to rookie Jacoby Brissett before Brady returned from his suspension in Week 5. In Super Bowl LI, Garoppolo was active for the Patriots' 34–28 overtime victory over the Atlanta Falcons; he was the only active Patriot who did not play any snaps.
In the 2017 offseason, Garoppolo was the subject of several trade rumors, with the Chicago Bears and Cleveland Browns being cited most commonly as potential suitors. Ultimately, no trade occurred and Garoppolo remained with the Patriots.