Fister attended Merced College from 2003 to 2004. At Merced, he was a two-year letterman and participated in the 2003 Junior College All-Star Game. In 2003, he was a preseason All-American. Fister was drafted by the San Francisco Giants in the 49th round of the 2004 Major League Baseball draft but chose to transfer to Division I Fresno State University, where he played for the Bulldogs. In 2005, Fister led Fresno State with wins (7) and was second on the team in innings pitched (93⁄3) and strikeouts (77). He also appeared in 26 games at first base in 2005. That season, he was drafted by the New York Yankees in the sixth round but chose to stay at Fresno State for his senior season. In 2006, Fister had an 8-6 record and a 4.10 earned run average in 20 games. Following the season, Fister was drafted by the Seattle Mariners in the seventh round of the 2006 Major League Baseball draft.

Fister was selected by the Seattle Mariners in the seventh round of the 2006 Major League Baseball draft, and signed on June 10, 2006. He began his professional career that season with the Class-A Short-Season Everett AquaSox of the Northwest League. Fister went 3–5 with a 2.25 ERA, four saves, and 35 strikeouts in 20 games; four starts. He was first on the AquaSox in games finished (13), and ERA; tied for second in saves, and wins; and was third among pitchers in games played (20). The next season, 2007, Fister played with the Double-A West Tenn Diamond Jaxx of the Southern League. That season, he went 7–8 with a 4.60 ERA, one complete game, and 85 strikeouts in 24 games, all starts. Fister led the Diamond Jaxx pitching staff in wins, and home runs allowed (14); was tied for first in complete games; was second in hits allowed (156); and was third in losses, games started, innings pitched (131), runs allowed (78), and earned runs allowed (67).

Fister continued to play for the Double-A West Tenn Diamond Jaxx in 2008. On April 23, Fister was named the Southern League Pitcher of the Week. Fister became the Southern League’s first 10-game loser on July 10. On the season, Fister went 6–14 with a 5.43 ERA, and 104 strikeouts in 31 games; 23 starts. Fister was first among Diamond Jaxx pitchers in losses, games started, innings pitched (134⁄3), hits allowed (155), runs allowed (95), earned runs allowed (81), home runs allowed (12); and was second in wins, bases on balls (walks) allowed (45), and strikeouts. He was also first in the Southern League in runs allowed; and was second in losses, and earned runs allowed. At the end of the 2008 regular season, Fister played in the Arizona Fall League (AFL) with the Peoria Javelinas. In the AFL, Fister was involved in no decisions with a 3.32 ERA, and 22 strikeouts in 11 games, all in relief.

In 2009, Fister began the season with the Double-A West Tenn Diamond Jaxx for the third time in his career. However, he was later promoted to the Triple-A Tacoma Rainiers, and eventually the Seattle Mariners.

In 2010, Fister started the first game for the Mariners in spring training. Going into the season, Fister, and fellow starting pitchers Garrett Olson, Luke French and Jason Vargas competed for the Mariners’ fifth spot in the starting rotation. Fister ended up getting a job in the rotation (as did Vargas). 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. 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.”

Fister threw four pitches, and was mainly a groundball pitcher. His two seam fastball was thrown at 88–91 miles per hour (142–146 km/h). His other pitches were a cutter (85–87 miles per hour (137–140 km/h)), a curveball (73–79 miles per hour (117–127 km/h)), and a changeup (80–84 miles per hour (129–135 km/h)). The curveball was his best swing-and-miss pitch, with a career whiff rate of over 30%. Fister finished third and fourth in 2010 and 2011, respectively, in lowest walks per nine innings ratio.

In 2011, Fister was the Mariners’ number three starter behind Félix Hernández and Jason Vargas.

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. On August 17, the Tigers sent former first round pick Chance Ruffin to the Mariners to complete the trade. Before being dealt to the Detroit Tigers, Fister had a 3–12 record with a 3.33 ERA in 21 starts.

Fister was injury-free in 2013, making 32 starts for the Tigers. He set career highs in wins (14), win percentage (14-9, .609) and strikeouts (159), while finishing the regular season with a 3.67 ERA.

Following the 2013 season, Fister was named a finalist for the Gold Glove Award for the pitcher position alongside Mark Buehrle and R.A. Dickey. Fister finished the season with zero errors for a perfect 1.000 fielding percentage. Additionally, he led all American League pitchers in putouts (23) and double plays started (5), and was seventh in assists (29).

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

Fister pitched in 25 games for the Nationals in 2015, 15 of which were starts. He posted a 5–7 record, 4.19 ERA, and 63 strikeouts in 103 innings pitched.

On January 28, 2016, Fister signed a one-year, $7 million contract with the Houston Astros. He became a free agent at the end of the season.

On May 20, 2017 Fister signed a minor-league contract with the Los Angeles Angels. On June 21, 2017 he opted out of his Angels contract and was placed on waivers.

On June 23, 2017, Fister was claimed off waivers by the Boston Red Sox. On June 25, Fister made his first start with the Red Sox, going 6 innings and striking out 6 batters, allowing 3 earned runs and in a 2-4 loss against the Los Angeles Angels. 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. On February 13, 2019, Fister retired.