After going unselected in the Major League Baseball (MLB) draft out of high school, deGrom enrolled at Stetson and played for the Hatters. He was exclusively a shortstop during his freshman and sophomore seasons. Though he was considered a good fielder with a strong throwing arm, deGrom was a light hitter, with a career .263 batting average. He made his first appearance as a pitcher in May 2009. In the summer of 2009, between his sophomore and junior years, deGrom received an invitation to play collegiate summer baseball for the DeLand Suns of the Florida Collegiate Summer League, which he declined after discovering that they wanted him to play as a pitcher.

The New York Mets selected deGrom in the ninth round as a pitcher, with the 272nd overall selection, of the 2010 Major League Baseball draft. He signed with the Mets, receiving a $95,000 signing bonus. The Mets assigned deGrom to the Kingsport Mets of the Rookie-level Appalachian League, where he made six starts before he was diagnosed with a partial tear of the ulnar collateral ligament (UCL) in his pitching elbow. He attempted to rehabilitate his arm for four months, but underwent Tommy John surgery to repair the UCL in October. He did not pitch in 2011 while he recovered from the surgery. While rehabilitating, deGrom worked on his changeup with Johan Santana.

DeGrom pitched for the Savannah Sand Gnats of the Class A South Atlantic League and the St. Lucie Mets of the Class A-Advanced Florida State League in 2012, finishing the year with a 2.43 ERA in 19 games started. In 2013, he began the season with St. Lucie, but was promoted to the Binghamton Mets of the Class AA Eastern League after two starts due to injuries to Binghamton’s Luis Mateo and Cory Mazzoni. He received a promotion to the Las Vegas 51s of the Class AAA Pacific Coast League in June after the Mets promoted Zack Wheeler and Carlos Torres to the major leagues and traded Collin McHugh. He had a combined 4.51 ERA for the season, due to a broken finger suffered during the offseason, which altered the way he threw the ball.

The Mets added deGrom to their 40-man roster on November 20, 2013, to protect him from being eligible in the Rule 5 draft. During the offseason, deGrom improved his mechanics, and learned to throw a curveball. He began the 2014 season with Las Vegas, and had a 4–0 win–loss record and a 2.58 ERA in his first seven games started.

The Mets promoted deGrom to the major leagues on May 12, 2014, after Gonzalez Germen was placed on the disabled list. The Mets planned to use deGrom in relief, but an injury to Dillon Gee required the Mets to insert him into their starting rotation. DeGrom made his major league debut on May 15 against cross-town rival New York Yankees in Citi Field. He faced fellow rookie Chase Whitley, also making his MLB debut. He pitched seven innings, allowing only one run and striking out six, but the Yankees shut out the Mets and won 1–0. DeGrom also collected his first MLB hit in the game in his first career at bat. It was the first hit by a Mets pitcher in the 2014 season ending an 0-for-64 hitless streak, the worst collective mark by a pitching staff to begin a season in MLB history.

On September 15, 2014, deGrom faced the Marlins and struck out his first eight batters, tying the MLB record. Near the end of the season, deGrom was shut down for the year, ending his season with a 9–6 record, a 2.69 ERA and 144 strikeouts. DeGrom won the 2014 Sporting News NL Rookie of the Year Award and was named the NL Rookie of the Year by the Baseball Writers’ Association of America (the first by a Met since Dwight Gooden in 1984), receiving first place votes on 26 of the 30 ballots.

Shortly after graduating from high school, deGrom met his wife, Stacey. They were married in November 2014, and live in DeLand, Florida. They have a Morkie, and had their first son, Jaxon, in April 2016. Their second child, a daughter named Aniston, was born in February 2018.

DeGrom and Clayton Kershaw of the Los Angeles Dodgers were selected as NL Co-Players of the Week for the week ending June 7, 2015. He began the 2015 season with an 8–6 win-loss record and a 2.30 ERA through the end of June, and was named to the NL roster in the 2015 MLB All-Star Game. During the All-Star Game, deGrom struck out the three batters he faced on ten pitches, becoming the first person to do so since pitch counts were recorded. DeGrom pitched to a 14–8 record with a 2.54 ERA and a 0.99 walks plus hits per inning pitched ratio during the 2015 season.

At Stetson, deGrom began to grow out his hair. His starts with the Mets led to the trending hashtag on Twitter of “#hairwego”. His hair inspired a promotional “Jacob deGrom Hair Hat” giveaway at Citi Field during the 2016 season. After learning that an unnamed MLB hitter said that deGrom’s hair made it harder to pick up the ball out of his hand, deGrom said in 2016 that he would never cut his hair. However, he cut his hair during the 2017-18 offseason, saying that doing so could add speed to his fastball, and also that he was tired of having long hair. Notably, deGrom has won the NL Cy Young Award twice since cutting his hair.

On June 18, 2017, deGrom hit his first career home run at Citi Field against Joe Ross of the Washington Nationals. deGrom was named NL Player of the Week for the week of June 12–18 after hitting his first home run, posting a 0.53 ERA, allowing eight hits, striking out 12 and walking six in 17 innings over two starts. deGrom recorded wins in eight consecutive starts from June 12 until July 24, tying a franchise record previously set by Seaver, David Cone and Bobby Jones. deGrom recorded the first stolen base of his career on August 4 off of Yu Darvish and Yasmani Grandal of the Dodgers. He became the first Mets pitcher to steal a base since Óliver Pérez in 2008.

During the 2018-19 offseason, the Mets hired Van Wagenen as their general manager. DeGrom and the Mets agreed to a $17 million salary for the 2019 season, the largest annual raise ever for an arbitration-eligible player. With Van Wagenen now negotiating for the Mets rather than deGrom, the two sides agreed to a five-year, $137.5 million contract extension with an option for the 2024 season during spring training in 2019. DeGrom started for the Mets on Opening Day against Max Scherzer, the 2018 Cy Young Award runner-up to deGrom and the 2017 Cy Young Award winner. DeGrom set a career high in strikeouts in his next start on April 3 with 14. deGrom began the first half of the 2019 season with a 4–7 record and a 3.27 ERA while striking out 138 batters. He was then named to the NL roster in the 2019 Major League Baseball All-Star Game. DeGrom had a remarkable second half, posting a 7–1 record with a 1.44 ERA and 117 strikeouts. He won his second straight Cy Young Award in a near-unanimous vote, receiving 29 of 30 first-place votes, becoming the 11th pitcher in history to win back-to-back Cy Young Awards.

In December 2019, the New York Post named him their New York Athlete of the Decade over such competition as Eli Manning, Henrik Lundqvist, Mariano Rivera and Derek Jeter.