The four-time French champions, chasing an unprecedented fifth successive title, remain 12 points clear of second-placed Auxerre, who entertain Nancy on Saturday.
Last season's surprise runners-up Lille, who produced a superb performance, climb to fourth and are now 14 points off the pace heading into the winter break.
"First of all, congratulations to Lille, who played a great match," said Lyon coach Gerard Houllier, whose team's only previous defeat in a competitive match this season was against Nantes on penalties in a French League Cup tie in October.
"We were not aggressive enough in the first half," the former Liverpool manager added. "We played better in the second half but we allowed them too much space. Maybe we were a bit tired. This does not erase what we achieved previously."
Lyon have been shining not only at home but also in Europe with a great run featuring a stunning 3-0 defeat of Real Madrid in the group stage of the Champions League.
They were paired with PSV Eindhoven in the last 16 in Friday's draw and dream of going all the way to a final that will be played at the Stade de France.
LILLE REWARDED
Lille showed more initiative in the opening stages and were rewarded after nine minutes when Nigerian striker Peter Odemwingie opened the scoring from the edge of the box.
Lyon stepped up a gear after the break and had created several chances when midfielder Mathieu Debuchy doubled Lille's advantage from a counter-attack in the 62nd minute.
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Forward Sidney Govou reduced the arrears in the 68th minute with an angled shot from just outside the area but Lille soon restored a two-goal lead with a header from a free kick by midfielder and captain Stephane Dumont two minutes later.
"We played with no fear," said Lille coach Claude Puel. "Lyon may have the better team but we know we're good enough to give anybody a hard time."
Lille were earlier drawn to play Ukrainian side Shakhtar Donetsk in the first UEFA Cup knockout round after failing to negotiate the group stage of the Champions League.