On September 20, 2016, the Indians purchased Plutko's contract from the Clippers and added him to their active roster.[14] In 28 starts for Akron and Columbus prior to his call up, he pitched to a 9–8 record and 3.73 ERA. He made his major league debut on September 24 as a relief pitcher.[15]
Plutko spent all of 2017 with Columbus, going 7–12 with a 5.90 ERA in 24 games (22 starts).[16] He began 2018 with Columbus, and was recalled on May 3 for one game. He was optioned back to Columbus the day after. He was recalled once again on May 23 to take over as the fifth starter for Cleveland after Josh Tomlin was moved to the bullpen.[17] He was sent back to Columbus, and threw a no-hitter on June 2.[18] He finished with a record of 4–5 in 17 games (12 starts). The following season, Plutko was 7–5 in 109+1⁄3 innings.
Before the 2020 season, Plutko was moved to the bullpen. He got a spot start in the second game of a doubleheader against the White Sox, where he went six innings and struck out four while allowing two runs.[19]
With the 2020 Cleveland Indians, Plutko appeared in 10 games, compiling a 2–2 record with 4.88 ERA and 15 strikeouts in 27+2⁄3 innings pitched.[20]
Baltimore Orioles
On March 27, 2021, Plutko was traded to the Baltimore Orioles in exchange for cash considerations.[21] In 38 games for Baltimore, Plutko posted a 6.71 ERA with 44 strikeouts. On August 15, 2021, Plutko was designated for assignment by the Orioles.[22] On August 19, Plutko cleared waivers and was assigned outright to the Triple-A Norfolk Tides.[23] On October 4, Plutko elected free agency.[24]
LG Twins
On December 9, 2021, Plutko signed a one-year contract worth $500,000, with an additional $300,000 in achievable incentives, with the LG Twins of the KBO League.[25] He had a 15-5 record and a 2.39 ERA for the Twins.[26] On December 2, 2022, Plutko re-signed with the Twins on a one-year contract for the 2023 season worth $1.4 million.[27] In 21 starts for the team, he logged an 11–3 record and 2.41 ERA with 101 strikeouts across 123+1⁄3 innings pitched. On October 27, 2023, Plutko left Korea following a left hip injury.[28] He became a free agent following the season and announced he was hoping to return to Major League Baseball.[29]
Minnesota Twins
On May 3, 2024, Plutko signed a minor league contract with the Minnesota Twins.[30]