[2][3][4] Garoppolo was selected in the second round of the 2014 NFL draft by the New England Patriots, where he spent his first four seasons as Tom Brady's backup and was a member of two Super Bowl-winning teams.

Traded to the San Francisco 49ers near the end of the 2017 season, Garoppolo helped revitalize a 1–10 team by winning the five remaining games that year.

[14] In his first year, Garoppolo 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.

[29] He was the first player from the Football Championship Subdivision drafted in 2014, and the highest-drafted quarterback the Patriots had selected since Drew Bledsoe was picked first overall in 1993.

[31][32] In 2014, Garoppolo made his regular season debut in the fourth quarter of the Patriots' Week 4 41–14 road loss to the Kansas City Chiefs.

[40] It was later revealed that Garoppolo 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.

[43][44] During the offseason, Garoppolo was the subject of several trade rumors with the Chicago Bears and Cleveland Browns being cited most commonly as potential suitors.

[48] Garoppolo made his 49ers debut on November 26 in the final minute of the 49ers' Week 12 matchup against the Seahawks, taking his first snaps of the season after starter C. J. Beathard suffered a leg and hip injury.

[54] In the regular season finale against the Los Angeles Rams, who were resting most defensive starters to prepare for the playoffs, Garoppolo accumulated 292 passing yards, two touchdowns, and two interceptions in a 34–13 blowout 49ers' win.

At the time of its signing, it was the largest contract in NFL history on an annual basis, surpassing that of Detroit Lions quarterback Matthew Stafford.

[63] During a Week 3 38–27 road loss to the Chiefs, Garoppolo finished with 251 passing yards for two touchdowns before leaving the game with a left knee injury.

[76] Garoppolo was the runner-up for NFL Comeback Player of the Year, finishing one vote behind Titans quarterback Ryan Tannehill.

[78] Hampered by a knee injury, Garoppolo attempted only eight passes in the 37–20 NFC Championship victory over the Packers, the fewest in a postseason game since Bob Griese in Super Bowl VIII, completing six for 77 yards.

[82] In the next game against the New York Jets, Garoppolo had 131 passing yards and two touchdowns before leaving the eventual 31–13 road victory following the first half with an ankle sprain and was replaced by Nick Mullens.

[88] In the next game against the Seahawks, Garoppolo completed 11 of 16 passes for only 84 yards and an interception before leaving the eventual 37–27 road loss during the fourth quarter with an ankle injury and being replaced by Mullens.

[93] He was designated to return from injured reserve on December 22, and began practicing with the team again, but the 49ers did not activate Garoppolo before the end of the season.

[100] In the regular-season finale against the Rams, Garoppolo threw for 316 yards, a touchdown, and two interceptions, but helped the 49ers rally from being down 17–3 at halftime and won on the road 27–24 in overtime, sending the team to the playoffs.

[104] In the Divisional Round, he threw for 131 yards and an interception en route to a 13–10 upset road victory over the heavily favored Packers.

[105] During the NFC Championship against the Rams, Garoppolo had 232 passing yards and two touchdowns, but threw a costly interception to Travin Howard in the final two minutes in the 20–17 road loss.

[110] In the next game against the Denver Broncos, he had 211 passing yards, a touchdown, and an interception while also stepping out of the back of the end zone, committing a safety during the narrow 11–10 road loss.

[113] During a Week 13 33–17 victory over the Dolphins, Garoppolo threw for 56 yards before injuring his foot in the first quarter and was initially expected to undergo surgery, which would prematurely end his season.

Without Garoppolo, the 49ers finished the season with a 13–4 record, but lost to the Eagles in the NFC Championship Game on the road 31–7 after injuries to both Brock Purdy and Josh Johnson.

On October 31, 2023, Garoppolo was benched in favor of rookie Aidan O'Connell, after leading the NFL in interceptions and missing two games for a subpar 3–5 start to the year.

While Garoppolo was active from Week 3 onward, he did not see the field until the regular season finale, when the Rams opted to rest Stafford and most other starters with their playoff berth secured.