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."
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.
"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.
"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.
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.
