The San Francisco Giants selected Wheeler sixth overall in the 2009 MLB Draft, and he elected to sign with the team rather than honor his previous college baseball commitment for Kennesaw State.

[5] As a junior in 2008, Wheeler posted an 8–3 win–loss record, with a 1.31 earned run average (ERA) and 127 strikeouts in 64+1⁄3 innings pitched, and was named the Georgia High School Association 4A Region Pitcher of the Year.

[13] Prior to the 2011 season, Baseball America named Wheeler the number two prospect in the Giants organization, and declared that he had the "best fastball" in the farm system.

[14] On July 28, 2011, the Giants traded Wheeler to the New York Mets in exchange for veteran outfielder Carlos Beltrán and cash.

[19] The following day, the Mets clarified that, despite his pitching performance in Double A, he was not being considered for a major league promotion, and that the rotation spot abdicated by Dillon Gee would be filled by either Matt Harvey or Miguel Batista.

In 149 innings between Binghamton and Buffalo, Wheeler posted a 12–8 season record with a 3.26 ERA and led Minor League Baseball with 148 strikeouts.

Mets general manager Sandy Alderson told reporters that Wheeler was expected to open the 2013 season with Buffalo and that he would likely make his major league debut that same year.

[23] After the Bisons chose to reaffiliate with the Toronto Blue Jays during the 2012 offseason,[24] Wheeler and other Mets Triple-A prospects began pitching in 2013 for the Las Vegas 51s of the Pacific Coast League, which was infamous at the time for its exceptional batting and, by extension, difficulty for pitchers.

[25] Wheeler stumbled at the beginning of the season, accumulating a 6.34 ERA in his first three starts with Las Vegas, but began to find his rhythm after striking out eight batters in 6+2⁄3 innings against the Reno Aces on April 30.

[12] Wheeler made his major league debut on June 18, 2013, pitching six shutout innings in the second game of a doubleheader against the Atlanta Braves.

[30] With the news that Matt Harvey would miss the 2014 season to recover from Tommy John surgery, some sports journalists expected Wheeler to become the Mets' ace.

[30] On March 16, 2015, the Mets announced that Wheeler had torn the ulnar collateral ligament in his right elbow, an injury that was diagnosed after he began experiencing discomfort during spring training.

[35] Shortly after the announcement, sources reported that Wheeler had torn a tendon in the same elbow during the previous season, and that he had undergone platelet-rich plasma therapy to hasten the healing process.

In early April 2016, he underwent a second surgery to remove an undissolved stitch in his elbow, and the Mets pushed his expected return to after the MLB All-Star break.

[40] Finally, in mid-August, Wheeler was shut down after being diagnosed with a strained flexor tendon, which required another platelet-rich plasma injection.

[55] As he was set to become a free agent at the end of the 2019 season, there were rumors that the Mets would attempt to trade Wheeler before the July 31 deadline, but they instead elected to retain him, with then-general manager Brodie Van Wagenen telling reporters, "We think he's a good pitcher.

[61] Wheeler finished the pandemic-shortened 2020 season with a 4–2 record and 2.92 ERA in 11 games and 71 innings, and led the NL in batters hit by pitch with 7.

In his season debut on April 3, Wheeler struck out 10 batters in 7 innings, the first time he recorded a double-digit number of strikeouts with the Phillies.

[64] After posting a 2.05 ERA in his first 17 starts and leading the league with 139 strikeouts in 114 innings pitched, Wheeler received his first MLB All-Star Game selection in 2021.

[65] When Mets ace and former teammate Jacob deGrom announced that he would not attend the All-Star Game, some fans speculated that Wheeler would be chosen to start for the National League team; the honor was ultimately given to Max Scherzer of the Nationals, with Wheeler making an appearance at the top of the ninth inning to strike out Matt Olson and retire the side.

[66] Wheeler led MLB with a career-high 213+1⁄3 innings, finishing the season 14–10 with a 2.78 ERA as well as a league-leading three complete games, two shutouts, and 849 batters faced.

[75] Baseball analysts consider Wheeler's four-seam fastball to be his best pitch, boasting a comparable release path to former Phillies ace Cole Hamels.

The change was similar to that of New York Yankees pitcher Gerrit Cole, whose pitching performance improved after abandoning his sinker.

[79] He considers the curveball to be "decent", and believes that his control of the pitch, which he has been throwing since high school, has decreased with the continued improvement of his slider.

[80] His changeup, by contrast, is a more recent pitch, one that Wheeler began throwing in the 2014 season to confuse batters expecting a hard fastball.

[82] Wheeler and his wife Dominique have two children, a son born July 20, 2020, shortly before the start of the pandemic-shortened 2020 MLB season, and a younger daughter.