Despite Romelu Lukaku being dropped to the bench after a dismal showing against Crystal Palace on Saturday, Chelsea needed just eight minutes to find the net through Havertz.
The reigning champion saw in-form duo Kovacic and Ziyech hobble off before the hour mark, casting doubt over their chances of featuring in the Carabao Cup final against Liverpool on Monday (AEDT).
WATCH the Carabao Cup final LIVE & ONLY on beIN SPORTS | Foxtel, Kayo Sports, Fetch TV & beIN SPORTS CONNECT
Pulisic finished off a quick break after 63 minutes to secure a strong first-leg lead for Thomas Tuchel's side, with the return leg to come in France next month.
Havertz wasted little time in making his mark as the central striker, nodding home from Ziyech's corner after failing to take a couple of early chances.
Antonio Rudiger almost turned a Renato Sanches cross into his own net and Lille threatened with a flurry of chances from the resulting corner as they started to get a foothold in the game.
Chelsea was dealt a blow when they lost Kovacic and Ziyech in quick succession early in the second half, but they doubled their advantage in the 63rd minute.
N'Golo Kante surged forward from inside the Chelsea half and fed Pulisic for a delightful dink over the onrushing Leo Jardim and into the bottom-right corner.
Lille tried to reduce the arrears with a push for a late goal, but Edouard Mendy was never really tested and Chelsea remained in charge of the tie.