[1] The Pittsburgh Pirates selected Holmes in the ninth round of the 2011 Major League Baseball draft.

[3][4] Holmes made his professional debut in 2012 with the State College Spikes and spent the whole season there, going 5–3 with a 2.28 ERA in 13 starts.

[5] He returned in 2015 and made three rehab starts with the Gulf Coast League Pirates before being assigned to the Bradenton Marauders.

He made his major league debut on April 6 against the Cincinnati Reds, pitching two innings in which he gave up one run on two hits while striking out two and walking none.

[15] On July 26, 2021, the Pirates traded Holmes to the New York Yankees in exchange for Diego Castillo and Hoy Park.

[15] He made his Yankee debut against the Tampa Bay Rays, shutting down the batters in order.

[18] Holmes notched his 29th consecutive game without allowing a run on June 18, setting a new Yankees franchise record for consecutive scoreless appearances, breaking Mariano Rivera's record set in 1999.

[23] Holmes struggled midseason and was removed from the closer role after giving up a walk-off grand slam to the Texas Rangers on September 3, his MLB-leading 11th blown save of the season.

[25] On December 9, 2024, Holmes signed a three-year, $38 million contract with the New York Mets including an opt-out after the 2026 season.