Ben Yedder scored with seven minutes left for the principality side, shortly after Strahinja Pavlovic was sent off, adding to Krepin Diatta's goal before halftime following Jonathan David's early double for the visitors.
The result put Monaco, who had not scored in their three previous competitive games, in seventh place with 19 points from 14 matches. Lille are two points behind in 12th, having won only four games in the league so far this season.
The hosts got off to a terrible start as David opened the scoring for Lille in the fifth minute with a penalty after Xeka was brought down by Pavlovic.
The Canadian doubled the advantage four minutes later when he was played through by Tiago Djalo and beat keeper Alexander Nuebel from close range.
Nuebel kept Monaco afloat by denying Jonathan Ikone and David twice before the visitors pulled one back four minutes before the interval as Diatta found the back of the net from the edge of the box with a powerful low shot.
Monaco, whose defence was completely overwhelmed, were lucky to be a single goal down at halftime.
Things got worse for them as Pavlovic picked up a second yellow card for a rough challenge on Ikone in the 78th minute.