[4] In his major league debut on May 18, 2015, McCullers allowed one run, three walks and three hits while striking out five batters in 4+2⁄3 innings and took a no-decision in the Astros' 2–1 loss to the Oakland Athletics.

In that same span, McCullers also became the first Astros pitcher since Nolan Ryan in 1984 to allow no earned runs over at least five innings pitched in each of four consecutive appearances.

[9] On October 21, 2017, McCullers pitched four scoreless innings in relief and earned his first career save in a 4–0 win over the New York Yankees in Game 7 of the ALCS.

[11] In a key moment in this game, after losing command and walking a batter, he threw 24 consecutive curveballs to retire the last six Yankees in a row.

[17] On November 6, 2018, McCullers underwent Tommy John surgery to repair a torn UCL in his right elbow and was ruled out for the entire 2019 baseball season.

[23] Following the regular season, the Houston chapter of the Baseball Writers' Association of America (BBWAA) named McCullers the Astros' team Pitcher of the Year, his first such award.

[25] He was unable to participate in the remainder of the playoffs, in the which the Astros reached the World Series, and were defeated by the Atlanta Braves in six games.

Still recovering from the forearm injury, McCullers was diagnosed with a right flexor tendon strain, and was unable to throw in spring training and missed the start of the 2022 season.

[26] On August 13, McCullers made his season debut and earned the win after hurling six shutout innings versus the Oakland Athletics.

[27] McCullers went 5+2⁄3 innings on September 2, allowing two runs, six hits, four walks and striking out seven to earn the win in a 4–2 final versus Los Angeles.

[29] On September 21, McCullers worked seven innings versus his hometown Tampa Bay Rays and was the winning pitcher, allowing two runs to lead the Astros in a 5–2 final score for the series sweep, their first-ever at Tropicana Field.

[31] In the third game of the 2022 ALDS, McCullers hurled the first six innings of a major league postseason-record 18-inning shutout and series-clinching sweep of the Mariners.

The game remained scoreless for an unprecedented 17 innings in postseason history—until rookie Jeremy Peña homered in the top of the 18th to eventually win it for the Astros, 1–0.

[35] On June 14, 2023, McCullers underwent season–ending surgery to repair the flexor tendon in his pitching arm and remove a bone spur.