Kai Havertz -- starting up front in place of benched Romelu Lukaku -- gave Chelsea an early lead within the first 10 minutes before U.S. men's national team forward Pulisic doubled the score after the hour mark.
"We knew it was a difficult game. They played very good football. The first half was difficult for us. It's half time now, and we have to win there as well," Havertz said after the game.
"We have a lot of good strikers, so it's always good to change, to not make it easy for the opponent. We didn't play our best football, it was hard, but the win is the most important thing, and it's another competition on Sunday [against Liverpool in the Carabao Cup final].
"We have a chance to win another trophy on Sunday, we hope to win this game."
It was a dominant start for Chelsea and Thomas Tuchel's side managed to capitalise on their early pressure through Havertz after just eight minutes.
Chelsea won a corner and Hakim Ziyech sent a the ball into the box. Havertz was there to head it into the net after missing two early chances.
Pulisic doubled their lead on 63 minutes when N'Golo Kante won the ball in the middle of the field and ran at the Lille defence.
He played the ball off to Pulisic on the edge of the box and the USMNT star struck it past Leo Jardim in the Lille goal.
Tuchel told reporters after the win over Lille that he had decided Lukaku needed a break after starting in a string of games recently.
"The focus was today on intensity, on a high-speed game and hard work off the ball," the German coach said. "Romelu struggled in the last games to deliver that."