He played in Major League Baseball (MLB) for the Colorado Rockies, Arizona Diamondbacks, Houston Astros and Washington Nationals.

As a member of the Astros, Harris was named an American League All-Star in 2016, won the 2017 World Series, and, in 2019, pitched in a combined no-hitter and an immaculate inning.

[5] He made his major league debut the next day, allowing 3 earned runs in 1.0 inning of work against the Milwaukee Brewers.

[14] During the 2019 regular season, he was 4–1 with four saves and a 1.50 ERA; over 68 relief appearances, he pitched 60 innings and struck out 62 batters.

[10] He set two single-season relief pitching franchise records in 2019—for ERA, and for inherited runners strand rate (97.7%).

[15] In Game 3 of the World Series, Harris entered the bottom of the sixth inning versus the Washington Nationals with one out and two runners aboard.

He proceeded to strand both runners and retire the side the following inning for a season-high five outs recorded on the way to a 4–1 Astros win.

[16] However, he surrendered the go-ahead home run to Howie Kendrick in Game 7 as the Nationals prevailed and won the World Series.

On January 3, 2020, the Washington Nationals announced they had signed Harris to a three-year guaranteed contract reportedly worth $24 million.

[18] Harris could not replicate his 2019 success with Houston in 2020, but still had a solid season with Washington, registering a 3.06 ERA with 21 strikeouts in 172⁄3 innings of work.

On February 10, 2023, Harris' wife, Caroline, posted a video on Instagram mentioning that he had retired from baseball after nearly a decade in MLB.