Corentin Tolisso's third-minute opener was cancelled out by Idrissa Gueye and Marcos Lopes's second-half goals as Lille handed Lyon their first defeat for 12 league games.
Lyon, who were last beaten at arch-rivals St Etienne on Nov. 30, have 54 points from 27 games and lead second-placed Paris St Germain, who travel to Monaco on Sunday, by two points.
Olympique de Marseille are in third spot, four points off the pace, after losing 3-2 at home to Caen on Friday.
"Next week we'll have to show more consistency against Montpellier," said Lyon coach Hubert Fournier.
Lyon were quickly in front on Saturday as Tolisso volleyed home from Nabil Fekir's corner.
Lille were lucky to be only one goal down at halftime with Ligue 1 top scorer Alexandre Lacazette the biggest culprit for the visitors.
The hosts, who are eighth on 35 points, stepped up a gear after the break and were rewarded in the 56th minute when midfielder Gueye netted from close range after playing a fine one-two with Lopes.
Midfielder Lopes scored four minutes later when he curled a superb shot past Anthony Lopes from just inside the box.
(Reporting by Julien Pretot, editing by Tony Jimenez)
