With Tommy Milone going on the disabled list, the Twins promoted Duffey to the major leagues to make his major league debut on August 5, 2015.[14] Duffey finished the season with a 5–1 record in 10 starts for the Twins and poising himself for a rotation spot in 2016.[citation needed] After starting the season in Triple–A due to a logjam in the rotation, Duffey was called up on April 24. Duffey recorded his first major league hit, a sacrifice bunt, that same day in National League play against the Washington Nationals.[15]
On June 26, 2016, Duffey took a perfect game through 5.2 innings until it was broken up by Aaron Hicks. The Twins would still win 7–1 over the Yankees.[16] Despite his 6.43 ERA, Duffey finished the season in the rotation, leading the team in wins as he went 9–12 in 26 starts.
In 2017, Duffey was moved to the bullpen and became exclusively a relief pitcher. He appeared in 56 games and amassed a record of 2–3 with a 4.94 ERA. He made the Twins' roster in 2018 in the same role. He was sent down multiple times throughout the season to Triple–A, having appeared only in 19 games for the Twins. Duffey was converted into a reliever for the 2019 season and excelled in the role, registering an ERA of 2.50 in 58 games.
With the 2020 Minnesota Twins, Duffey appeared in 22 games, compiling a 1–1 record with 1.88 ERA and 31 strikeouts in 24.0 innings pitched.[17]
On May 20, 2021, Duffey was suspended two games after throwing at Chicago White Sox catcher Yermín Mercedes in a game on May 18.[18] He made 64 total appearances for Minnesota in 2021, registering a 3.18 ERA with 61 strikeouts and 3 saves in 62+1⁄3 innings pitched.
Duffey made 40 appearances out of the bullpen for Minnesota in 2022, logging a 4.91 ERA with 39 strikeouts and 2 saves in 44.0 innings of work. On August 5, 2022, Duffey was designated for assignment by the Twins.[19] He was released by the Twins organization on August 7.[20]
Texas Rangers
On August 12, 2022, Duffey signed a minor league contract with the Texas Rangers organization.[21] He made 4 scoreless appearances for the Triple–A Round Rock Express and struck out five in five innings pitched. On August 28, Duffey opted out of his contract and became a free agent.[22]
New York Yankees
On August 30, 2022, Duffey signed a minor league deal with the New York Yankees.[23] He made seven appearances for the Triple-A Scranton/Wilkes-Barre RailRiders, struggling to a 10.50 ERA and 1–1 record with eight strikeouts in 6.0 innings pitched. He elected free agency following the season on November 10.[24]
Chicago Cubs
On January 27, 2023, Duffey signed a minor league contract with the Chicago Cubs organization.[25] He made 18 appearances for the Triple-A Iowa Cubs, posting a 4-0 record and 4.43 ERA with 24 strikeouts in 22+1⁄3 innings pitched. On June 1, Duffey exercised the opt-out clause in his contract, giving the Cubs 48 hours to add him to their 40-man roster or grant him his release.[26] The Cubs declined to add Duffey to their roster, and he was formally released on June 3.[27] He re-signed with the Cubs on a new minor league contract on June 16.[28] After posting a 3.77 ERA in 36 appearances for Iowa, the Cubs selected Duffey's contract to the major league roster on October 1.[29] He became a free agent following the season.
Kansas City Royals
On December 7, 2023, Duffey signed a minor league contract with the Kansas City Royals.[30] He began the 2024 season with the Triple–A Omaha Storm Chasers, logging a 3.24 ERA across 6 games. On April 22, 2024, the Royals selected Duffey's to the major league roster.[31] In 9 games for Kansas City, Duffey compiled a 5.00 ERA with 10 strikeouts across 9 innings pitched. He was designated for assignment by the team on May 24.[32] Duffey cleared waivers and was sent outright to Omaha on May 29.[33] He was released by the Royals organization on August 6.[34]