Ivory Coast striker Gervinho scored his second goal of the night one minute into stoppage time after being set up by substitute Eden Hazard.
Lyon, who twice blew a two-goal lead, dropped to fourth with 26 points from 15 matches, five behind Bordeaux, 1-0 winners over Paris St Germain on Saturday.
"It was our best game of the season. We were awesome," Gervinho told French TV Canal Plus.
"We concede too many goals. Enough is enough", said Lyon keeper Hugo Lloris.
The visitors got off to a dream start with Lopez flicking the ball past Mickael Landreau after being set up by Kim Kallstrom in the second minute.
The Argentine made it two 19 minutes later by converting a penalty after Ludovic Obraniak handed the ball in the area.
Lille, however, did not give up and reduced the arrears through Pierre-Alain Frau, who netted from close range after Lloris had failed to block a Yohan Cabaye header.
But Lopez scored his eighth goal of the season 10 minutes before the interval with a powerful strike from just inside the box.
Gervinho flicked the ball past Lloris nine minutes into the second half to give his side some hope, and Lille were rewarded for their efforts when Mathieu Debuchy was brought down in the box by Lamine Gassama.
Cabaye converted the penalty kick to level and Gervinho just had to tap in from a Hazard cross to give his side a deserved win.
Earlier, a Nicolas Dieuze late goal gave bottom club Grenoble their first victory of the season when they beat Toulouse 1-0 at home.
Grenoble are on six points, still a distant nine from safety.
AJ Auxerre, who briefly occupied top spot two weeks ago, slipped to fifth after losing 3-1 at home to strugglers Nancy.
Elsewhere, 10-man Boulogne showed great resilience in a 2-1 comeback home win against RC Lens, who were on a three-match winning streak.
