Pulisic had to leave the field just before halftime, which meant Milan played with 10 men for the last few minutes of the first half. Alejandro Jiménez took his place for the second half.
The 26-year-old went down after a challenge from Como's Marc-Oliver Kempf, immediately signaling for medical help and seemingly indicating an issue with his left thigh.
It's unclear if he'll be fit for Milan's upcoming match against Juventus on Saturday.
This injury comes right after Pulisic made his return from a previous setback, having played in the Italian Super Cup, which Milan won. He had been sidelined for almost a month due to a calf muscle tear and a minor ankle problem.
Pulisic scored in both the semifinal and final of the Super Cup and has been a standout for Milan this season, racking up five goals and four assists in Serie A, along with three goals in the Champions League.
Milan managed to secure a 2-1 victory against Como.