Centre-back Aurelien Chedjou headed the visitors in front following a Dimitri Payet corner in the 28th minute and Florent Balmont scored on the stroke of half-time, also from a pass by Payet who has now set up ten goals and scored seven.
Both sides conceded penalties in the second half with Salomon Kalou netting the third for Lille five minutes after the break and Lisandro Lopez making it 3-1 in the 57th.
Lyon failed to challenge Lille's domination and Payet went close to grabbing a fourth for the visiting team when his powerful effort hit the post with 11 minutes left.
"We failed in a big game tonight. We were poor. We have to accept it and quickly get back to work," centre-back Milan Bisevac told Lyon's website.
His coach Remi Garde added: "We are having harder times. We faced a really good team who bothered us."
Lyon, who lost 3-1 at Ajaccio last weekend, stayed second on 45 points from 24 games, six adrift of PSG who beat Bastia 3-1 on Friday. Lille are 10th on 34.
Third-placed Marseille, who are two points behind, conceded a penalty and finished with nine men as their poor run continued with a 1-1 draw at relegation-threatened Evian Thonon Gaillard on Sunday.
Andre-Pierre Gignac put the visitors in front with a superb half-volley in the 50th minute but Yannick Sagbo levelled for the hosts from the penalty spot following right-back Kassim Abdallah's dismissal for a foul on Saber Khlifa.
Marseille, who had Joey Barton sent off when they lost at home to bottom club Nancy last weekend, were reduced to nine men after Jordan Ayew picked up two bookings in two minutes, seconds after replacing Mathieu Valbuena.
"When you already received a yellow card, you have to take care and behave," Marseille coach Elie Baup told French channel beIN Sport, criticising Ayew who earned his second card for a rough challenge on Pavel Ninkovic.
Marseille, level on points with leaders Paris Saint-Germain after 19 games, stayed third on 43 from 24 matches, eight adrift of the capital club.
"We never said we were fighting for the title. Our goal remains fifth place albeit our good results until the winter break had given us hope of a top-three finish," Baup said following Marseille's poor recent form.
Marseille, who occupy the third Champions League qualifying spot, are three points ahead of Saint-Etienne in fourth and Stade Rennes, who climbed to fifth with a 2-0 home win over Toulouse.
Forward Romain Alessandrini, named in the France squad for the first time this week but who did not feature in the 2-1 loss to Germany, took advantage of goalkeeper Ali Ahamada's blunder to break the deadlock in the 79th minute with his 10th league goal of the season.
Striker Mevlut Erding doubled the lead from close range five minutes later for the home team, who have scored two goals in all their five last games in all competitions.
Evian climbed to 17th on 23 points, level with 18th-placed Sochaux in the 20-team standings.
