He played in Major League Baseball (MLB) from 2003 to 2019 for the Los Angeles Dodgers, Tampa Bay Devil Rays / Rays, Detroit Tigers, Arizona Diamondbacks, Chicago White Sox, St. Louis Cardinals, Washington Nationals, Chicago Cubs, Atlanta Braves, Miami Marlins, San Diego Padres, Baltimore Orioles, Oakland Athletics, and Toronto Blue Jays.

In that game, he pitched six innings, giving up one run and out-pitching Cy Young Award-winner Randy Johnson to earn his first career major league victory.

His season highlight came in a start against the Texas Rangers on August 11, in which he recorded a shutout, allowing only four hits and one walk while striking out eight.

[10] Jackson was selected to represent Detroit in the 2009 All-Star Game along with teammates Curtis Granderson, Justin Verlander, and Brandon Inge.

[11][12] At the end of July, opposing batters were hitting .216 against him, which was the lowest batting average in the league; he was followed by Matt Garza (.222), Jarrod Washburn (.224), and Scott Feldman (.228).

It was only the second no-hitter in Diamondbacks' history, the other being Randy Johnson's perfect game on May 18, 2004, as well as the fourth of the 2010 season, and the third time the Rays had been no-hit in less than 12 months.

[17] On July 30, 2010, the Diamondbacks traded Jackson to the Chicago White Sox for Daniel Hudson and David Holmberg.

On July 27, 2011, Jackson was traded to the Toronto Blue Jays with Mark Teahen for Jason Frasor and Zach Stewart.

The Blue Jays then traded Jackson to the St. Louis Cardinals later that day, along with Octavio Dotel, Marc Rzepczynski and Corey Patterson for Colby Rasmus, P. J. Walters, Trever Miller and Brian Tallet.

[20][21][22][23] On July 29, 2011, Jackson pitched his first game as a Cardinal and threw 7 strong innings, leading St. Louis to a 9–2 win over the rival Chicago Cubs.

Jackson declined a one-year salary arbitration offer from the Cardinals for the 2012 season, becoming a free agent in December 2011.

His final start against the Los Angeles Dodgers saw him give up 5 earned runs in just 2⁄3 of an inning, leading to his subsequent demotion to the bullpen for the remainder of the year.

Jackson entered 2015 competing for a spot in the starting rotation with Travis Wood, but lost after giving up 9 earned runs in 16+1⁄3 innings.

[35] Jackson recorded his first career save in relief of Matt Wisler on October 4, 2015, the final day of the season.

[41] After several outings with the Class-AAA Syracuse Chiefs, allowing just one earned run in 20+1⁄3 innings of work,[42] Jackson was promoted to the Nationals' major league roster to take injured starter Joe Ross' rotation spot for a July 18 start against the Los Angeles Angels of Anaheim.

[45] Jackson signed a minor-league contract with the Oakland Athletics on June 6, 2018, and was assigned to the AAA Nashville Sounds.

[46] He was called up to start for the Athletics on June 25, tying a Major League record of having played for thirteen different teams.

On July 22, 2019, Jackson signed a minor-league contract with the Detroit Tigers and assigned him to the Triple-A Toledo Mud Hens.

In two starts for the Mud Hens, Jackson allowed five earned runs on 11 hits in 7+2⁄3 innings, two strikeouts and four walks.

[56] On July 15, 2021, Jackson signed with the High Point Rockers of the Atlantic League of Professional Baseball, to help prepare for the 2020 Summer Olympics (contested in 2021).

[60] Jackson was one of a minority of MLB starting pitchers who relied almost exclusively on two pitches, a mid-90s fastball and an effective power slider.