He played in Major League Baseball (MLB) for the St. Louis Cardinals, Atlanta Braves, Minnesota Twins, New York Yankees, Toronto Blue Jays and Chicago Cubs.

He was chosen as the number five starter over fellow lefty Rich Hill, who started the season with the Memphis Redbirds in AAA, and Kyle McClellan, who returned to the bullpen for the Cardinals.

In his first start of the season, April 3 against the San Diego Padres, he threw his first MLB complete game shutout while striking out nine and giving up four hits in 102 pitches.

[4] On May 6, he took a perfect game into the eighth inning against the Milwaukee Brewers, before issuing a one-out walk to Casey McGehee, followed by a hit to Yuniesky Betancourt.

[6] On August 2, García hit his first career home run, a three-run homer off Brewers' starter Shaun Marcum.

For the 2011 season, García went 13–7, was second in the NL in complete games (two), shutouts (two), and wild pitches (12), and his .650 win–loss percentage was ninth best in the National League.

[2] The St. Louis Cardinals advanced to play the Texas Rangers in the World Series after defeating the Philadelphia Phillies and Milwaukee Brewers in the playoffs.

[10] In his fifth start of the season on June 8, García held the Toronto Blue Jays to seven scoreless innings to earn the win in a 5–0 victory.

[12][13] However, he informed the Cardinals on July 5 that he would have surgery on his left shoulder to correct thoracic outlet syndrome, ending his second consecutive season with fewer than ten starts.

In seven innings, he allowed one run and struck out four, with less than 90 pitches, but ended up with a 1–0 loss, bringing his record to 1–2 with a 2.70 ERA in his first three games.

[16] In a June 12 start against the Kansas City Royals, Jaime García netted his 500th career strikeout by getting Omar Infante as the Cardinals won 4–0.

[18] While carrying out his minor league rehabilitation assignment with the Peoria Chiefs on July 23, he pitched in a combined no-hitter and 2–0 win against the Clinton LumberKings, a Seattle Mariners affiliate.

[25] The 13 strikeouts were the most by a Cardinal lefty since Steve Carlton struck out 16 in 1970, with García posting a game score of 97, a season-high for MLB through that date.

[27] On December 1, 2016, the St. Louis Cardinals traded García to the Atlanta Braves for Chris Ellis, John Gant, and Luke Dykstra.

On July 24, 2017, the Braves traded García and Anthony Recker to the Minnesota Twins for prospect Huascar Ynoa.

[30][31] A free agent at season's end, García was reportedly involved in trade discussions before even making a start for Minnesota, as they were quickly falling behind Cleveland and Kansas City in the AL Central standings.

[33] On July 30, 2017, the Twins traded García and cash considerations to the New York Yankees in exchange for minor league pitchers Dietrich Enns and Zack Littell.

[34][35] Minnesota opted to pick up the remainder of García's $12 million salary for 2017, leaving New York to pay the pro-rated minimum.

[46] Four pitches comprised García's arsenal: fastball that reached approximately 90 miles per hour (140 km/h), curveball, slider and changeup.