After three years in the Blue Jays' farm system, Syndergaard was traded with several other prospects to the Mets in exchange for reigning Cy Young Award winner R. A. Dickey.

Syndergaard spoke with coaches for Oklahoma, Nebraska, and Baylor, but the only school willing to offer him a scholarship was Dallas Baptist University, where he committed to play for the Patriots as a batter, not a pitcher.

After seven appearances, during which he went 4–0 with a 1.41 ERA and struck out 37 batters in 32 innings,[12] he was promoted to the Class A Short-Season Vancouver Canadians of the Northwest League, by which point he could already reach pitch velocities up to 98 mph (158 km/h).

[12] On December 17, 2012, Syndergaard was traded to the New York Mets as part of a larger deal that allowed Toronto to acquire reigning Cy Young Award winner R. A. Dickey.

In addition to Dickey, the Blue Jays acquired catchers Josh Thole and Mike Nickeas in the trade, while the Mets received Syndergaard, Travis d'Arnaud, John Buck, and Wuilmer Becerra.

[19] Syndergaard joined the Class A-Advanced St. Lucie Mets of the Florida State League for the 2013 season, forming a starting rotation with Hansel Robles, Luis Mateo, Domingo Tapia, and Jacob deGrom.

[23] Syndergaard struggled in his first outing after the All-Star game, allowing three runs on seven hits against the Richmond Flying Squirrels, but recovered quickly, and in 11 starts for Binghamton, he was 6–1 with a 3.00 ERA and struck out 69 batters in 54 innings.

[24] Syndergaard was promoted to the Triple-A Las Vegas 51s for the 2014 season, winning his Pacific Coast League debut by striking out five batters in six innings of an 11–8 victory over the Fresno Grizzlies.

[28] Syndergaard opened the 2015 season in Las Vegas again, battling food poisoning and a forearm strain that April to post a 3–0 record and 1.82 ERA in his first five starts, as well as 34 strikeouts in 29+2⁄3 innings.

[29] When starting pitcher Dillon Gee was placed on the disabled list on May 8 with a strained groin, the Mets chose to call up Syndergaard over fellow top prospect Steven Matz.

[30] He made his MLB debut on May 12, holding the Chicago Cubs scoreless for five innings before allowing three hits in a row in the sixth, including a two-run home run from Chris Coghlan.

[32] When Gee returned from the disabled list on May 22, Mets manager Terry Collins decided not to move Syndergaard, instead saying that he would keep a six-man starting rotation that made room for both pitchers.

In doing so, Syndergaard joined Walt Terrell, Dwight Gooden, and Sid Fernandez as the only Mets pitchers to record three hits, including one home run, in a single game.

[39] On September 26, after defeating the Cincinnati Reds 10–2 at the Great American Ball Park, the Mets clinched their first NL East title and postseason appearance in nine years.

[41] Syndergaard made his first career appearance in relief for Game 5 of the NLDS, pitching a scoreless seventh inning in the 3–2 victory, helping to eliminate the Dodgers and send the Mets to the 2015 National League Championship Series (NLCS).

[52] The following week, Syndergaard was ejected from a Mets–Dodgers game after throwing a pitch behind the back of Chase Utley in a move that was believed to be retribution for a play during the NLDS that had fractured Ruben Tejada's leg.

[53] After struggling in a game against the Washington Nationals on June 27, lasting only three innings and squandering a 4–0 lead in the process,[54] Syndergaard revealed that both he and Steven Matz were experiencing bone spurs in their respective pitching elbows, while confirming that it was being treated with anti-inflammatory medication and was often painless.

[57] Syndergaard had a difficult stretch after the All-Star break, going winless in seven starts between July 3 and August 17 before pitching 5+2⁄3 innings in a 7–5 win against the Arizona Diamondbacks, during which he recorded another home run of his own.

[60] With Matz, Matt Harvey, and Jacob deGrom injured, Syndergaard was selected to start for the Mets in the 2016 National League Wild Card Game against the San Francisco Giants.

[63] Having spent spring training focusing on honing his two-seam fastball, Syndergaard was selected as the Mets' Opening Day starting pitcher for the 2017 MLB season.

[67] Syndergaard had previously declined to undergo medical imaging for his sore arm, instead taking the mound for his scheduled April 30 start, a 23–5 loss to the Washington Nationals during which he tore the torso muscle.

General manager Sandy Alderson told reporters that Syndergaard's physical rehabilitation was progressing well, and that having the pitcher "back on the mound if only for a moment relatively before the season ends" would help him mentally readjust to major league play.

[75] Pitching in six innings of the Mets' 9–4 victory over the St. Louis Cardinals, he became the second pitcher in franchise history to strike out 10 or more batters on Opening Day, following Pedro Martínez's rout of the Cincinnati Reds in 2005.

[81] After battling a sinus infection in the last week of September, Syndergaard closed the Mets' 2018 season with his first career complete game shutout, a 1–0 victory over the Miami Marlins.

[83] The first month of the season proved difficult for the Mets' entire starting rotation, with a combined 5.35 ERA among Syndergaard, deGrom, Wheeler, Matz, and Jason Vargas.

[38] During spring training in 2020, Syndergaard began to experience elbow discomfort, and he underwent an MRI exam at the suggestion of team athletic trainers when the 2020 MLB season was temporarily shut down due to the COVID-19 pandemic.

[100] Nearly two years after his last appearance for the Mets, Syndergaard returned to the major leagues on September 29, pitching a scoreless inning and striking out two batters in a 2–1 defeat of the Marlins.

[121][122] Syndergaard received the nickname "Thor" from Mets fans in 2013, when he posted a video on Twitter of himself weightlifting while wearing a Halloween costume of the Marvel Cinematic Universe character of the same name.

[129] In 2017, Syndergaard appeared in the Game of Thrones episode "The Spoils of War",[130] acting as a spearman for House Lannister who is eventually killed by one of Daenerys Targaryen's dragons.

The prank involved Syndergaard attempting to throw autographed baseballs to young fans in the stands, only for cast member Joe Gatto to steal the balls from the children.