He played in Major League Baseball (MLB) for the Seattle Mariners, Detroit Tigers, Washington Nationals, Houston Astros, Boston Red Sox, and Texas Rangers from 2009 through 2018.

Fister was selected by the Seattle Mariners in the seventh round of the 2006 Major League Baseball draft, and signed on June 10, 2006.

[4] He began his professional career that season with the Class-A Short-Season Everett AquaSox of the Northwest League.

[10] At the end of the 2008 regular season, Fister played in the Arizona Fall League (AFL) with the Peoria Javelinas.

[12] As a result, pitcher Jason Vargas was optioned to Triple-A Tacoma to make room for Fister on the Mariners' 25-man roster.

On April 19, Fister took a no-hitter into the seventh inning against the Baltimore Orioles until it was broken up by Nick Markakis' leadoff single.

[18] Although the Mariners suffered early season woes, the Seattle Post-Intelligencer praised Fister and fellow starter Jason Vargas as reasons for why the Mariners were not doing worse, stating, "If Doug Fister and Jason Vargas hadn't been excellent at the back end of the rotation, God knows where this club would be.

On July 30, 2011, Fister was traded to the Detroit Tigers along with relief pitcher David Pauley in exchange for Casper Wells, Charlie Furbush, Francisco Martinez, and a player to be named later.

Fister limited the Yankees to one run on five hits and two walks over five innings in the Tigers 3–2 victory, which sent them to the American League Championship Series.

[24] In Game 3 of the American League Championship Series, he held the Texas Rangers' offense to two runs in 71⁄3 innings to get the win in a 5–2 Tigers victory.

[26] The next day, Fister was placed on the 15-day disabled list with a strain of the costochondral muscle in his left side, an injury to the ribcage.

[28] In his next start on September 27, Doug set an American League record by striking out nine batters in a row against the Kansas City Royals.

Fister pitched in the second game of the ALDS against the Oakland A's, picking up a no decision in a 5–4 victory while giving up two runs in seven innings.

[31] Fister was struck in the head by a line drive off the bat of Giants outfielder Gregor Blanco during the second inning of Game 2 of the 2012 World Series.

Fister continued to pitch the game, holding the Giants to one run over six innings before turning it over to the bullpen.

[33] In Game 4 of the 2013 ALCS against the Boston Red Sox, Fister gave up just one run on eight hits, striking out seven over six innings and earning the win in a 7–3 Tigers victory.

[34] Following the 2013 season, Fister was named a finalist for the Gold Glove Award for the pitcher position alongside Mark Buehrle and R. A.

Additionally, he led all American League pitchers in putouts (23) and double plays started (5), and was seventh in assists (29).

[36] On December 2, 2013, Doug Fister was traded to the Washington Nationals for utility man Steve Lombardozzi Jr. and left-handed pitchers Ian Krol and Robbie Ray.

[37] During spring training with the Nationals, Fister developed a strained lat muscle on his right side that put him on the disabled list to start the 2014 season.

He bounced back in his next start, against the Arizona Diamondbacks, Fister gave up one earned run on five hits in seven innings.

On an August 22 start in Cleveland, Fister allowed a lead off home run to Francisco Lindor to briefly tie the score at 1–1, but this would turn out to be the only hit registered by the Indians as Fister would go on to pitch a complete-game 1-hitter and not allow a hit to the final 28 batters faced in the game in an eventual 9–1 Red Sox win.

On November 28, 2017, Fister signed a one-year, $4 million, contract with the Texas Rangers that included an option for the following season.