[7] Lugo made his Major League debut against the Chicago Cubs on July 1, 2016, throwing two shutout innings in a victory.

[8] On August 25, Lugo recorded his first major league win and hit, throwing five shutout innings against the St. Louis Cardinals at Busch Stadium before exiting with muscle cramps.

After injuries to other starters, Lugo found himself battling with Robert Gsellman for the final spot in the Opening Day starting rotation.

However, Lugo himself would be diagnosed with a partial tear of the ulnar collateral ligament in his pitching arm after competing for Puerto Rico in the 2017 World Baseball Classic.

[11] He returned to make his first start of the season for the Mets on June 11, 2017, against the Atlanta Braves, getting the win after pitching seven innings of one-run ball.

[12] He continued making shorter starts throughout September, finishing the season with a 7-5 record and an ERA of 4.71, with 85 strikeouts and 25 walks over 101+1⁄3 innings pitched.

He was once again effective in 2019, his first season in which he was exclusively a relief pitcher, posting a 2.70 ERA while striking out 104 batters and walking only 16 in 80 innings.

[16] On April 29, 2022, Lugo pitched in relief in a combined no-hitter against the Philadelphia Phillies, recording the last two outs of the top of the eighth inning.

[20][21][22][23] On July 21, 2024, Lugo threw his first career complete game; in 9 innings, he struck out 6 batters and allowed 3 hits, no walks, and one earned run in a 4-1 win over the Chicago White Sox.