The son of former big leaguer Lance McCullers was chosen by the Astros with the 41st pick in the 2012 draft. McCullers made 22 starts for Houston in his rookie season of 2015, going 6-7 with a 3.22 ERA and a 1.186 WHIP. Lance got the start in Game 4 of the divisional series against Kansas City and was in line for the win after allowing two runs on only two hits and two walks in 6-1/3 innings of work. Unfortunately, the Houston bullpen couldn't hold the lead and Kansas City went on to win the 2015 World Series.

He stepped up again in the 2017 postseason, pitching four innings of one-hit relief in Game 7 of the ALCS then starting Game 7 of the World Series which became a 5-1 clinching victory.

Tommy John surgery cost him the 2019 season but, over his first four years with the Astros, the Tampa, FL, native has posted a 29-22 record with a 3.67 ERA. He is expected to rejoin the Astros rotation in 2020.