He has previously played in MLB for the St. Louis Cardinals, New York Mets, Tampa Bay Rays, Boston Red Sox, and San Diego Padres.

Following a strong regular season, Wacha earned the 2013 National League Championship Series Most Valuable Player Award, after yielding one run and eight hits in his first 21 postseason innings pitched.

[7] During his freshman campaign, he made ten starts in 25 total appearances and posted a 2.90 earned run average and a 9–2 record.

[1] In his sophomore year, Wacha posted a 9–4 record in 16 starts with 123 strikeouts and just 20 walks and a 2.29 earned run average in 129+2⁄3 innings pitched.

He impressed team management and players alike, striking out 15 batters while only allowing one walk and one unearned run in 11+2⁄3 innings of work before being reassigned to the minor league camp.

[13] The Cardinals activated Wacha on May 30 to make his major league debut against the Kansas City Royals at Busch Stadium.

Wacha lost the chance for a win in the ninth, when Mitchell Boggs relieved and gave up a tying home run to the first batter he faced.

Wacha earned his first MLB win on June 11 as the Cardinals beat the New York Mets 9–2 at Citi Field.

[19] Three days after earning his first major league win, the Cardinals optioned Wacha back to Memphis to clear roster room for pitcher Jake Westbrook as he returned from the disabled list (DL).

On September 24, he pitched a no-hitter through 8+2⁄3 innings against the Washington Nationals that ended when Ryan Zimmerman stroked an infield single that glanced off Wacha's glove.

[24] Wacha finished his regular season in the Major Leagues appearing in 15 games, making nine starts and pitching 64+2⁄3 innings.

[26] Due to Wacha's back-to-back one-hit performances, Matheny announced that he would start Game 2 of the National League Championship Series (NLCS).

[29] Facing Kershaw again in Game 6, Wacha yielded just two hits in seven innings as his opponent unravelled in a 9–0 victory that sent the Cardinals to the World Series.

"[34] Before surrendering a home run to David Ortiz, Wacha tied Gibson with the longest scoreless streak (19 innings) in Cardinals' postseason history.

[35] Wacha became the 17th-youngest pitcher overall to win a World Series game and the second-youngest in Cardinals history behind only Paul Dean.

However, the Red Sox finally solved him, tagging him for six runs in 3+2⁄3 innings on their way to defeating the Cardinals for their eighth World Series title.

With 41 miles per hour (66 km/h) winds whipping, he struck out ten total in four innings but also walked five and required 93 pitches.

[42] A series of magnetic resonance imaging and computed tomography tests revealed an injury termed as a stress reaction in the scapula behind his throwing arm.

The stress reaction apparently was a case of the shoulder not repairing itself as fast as the strain from regular pitching had caused between the scapula bone and tendons.

With limited knowledge on the related biomechanical processes, the Cardinals training and medical staff researched methods to treat Wacha's injury and prevent the same course from happening again; likewise, they were uncertain of when he was to return to play.

[44] Wacha finished the 2014 season with a 5–6 record, a 3.20 earned run average, and a 1.20 walks plus hits per inning pitched in 19 starts.

He missed over a month due to right shoulder inflammation and finished the season with a 7–7 record in 27 games (24 starts) with a career-high 5.09 earned run average and 1.48 walks plus hits per inning pitched.

[50] On June 21, Wacha was placed on the 10-day disabled list due to a left oblique strain,[51] and did not pitch the remainder of the year.

[25] On November 27, 2021, Wacha signed a one-year contract with the Boston Red Sox, reportedly worth $7 million.

It was the 10th complete game 1–0 shutout in Red Sox franchise history, and the first since June 7, 2007, when Curt Schilling did so against the Oakland A's.

[60] On August 4, while on a rehabilitation assignment with the Worcester Red Sox, Wacha pitched 4+2⁄3 innings without allowing a hit against the Durham Bulls; Andrew Politi and Chase Shugart completed the combined no-hitter.

[66] On December 18, 2023, Wacha signed a two-year, $32 million contract with the Kansas City Royals which contained a player option for the second year.

Baseball Prospectus noted that his polish due to pitch command helped fast-track him to the Major Leagues.

Wacha offsets the shortage of sizable vertical movement with the pronounced descent through which his fastball, changeup and curve travel to create an additional obstacle as hitters to attempt square the bat on the pitch.

Although he could not remember the name of the restaurant (believed to be Fozzie's), he stated the Cracker Jack "added a little baseball flair to it".