Argentine striker Lisandro netted the winner in the 64th minute after Kim Kallstrom had cancelled out Joe Cole's opener. Lyon played with 10 men after Mouhamadou Dabo was sent off after 11 minutes.
Lille also finished the game with 10 men after Mathieu Debuchy picked up a second yellow card eight minutes from time as they succumbed to their first domestic defeat in five months.
Lyon will next travel to Lorient, who went through with a 1-0 win at Ligue 2 Le Mans earlier on Wednesday.
Nice saw off Dijon 5-3 on penalties after the game had ended in a 3-3 draw following extra-time and will travel to holders Olympique Marseille, who strolled past Caen with a 3-0 away win on Tuesday.
It was a much closer affair on Wednesday at Stade de Gerland.
France keeper Hugo Lloris blocked a deflected Florent Balmont attempt on his line as Lille looked the most dangerous side in a heated start to the game.
Dabo was shown a straight red card after only 11 minutes for a rough tackle on Laurent Bonnart.
Rio Mavuba had a clear chance in the 24th minute when he burst into the area, but the Lille captain skied his attempt over the bar.
The visitors went ahead three minutes later, when Eden Hazard set up Cole for the former England international to fire a 20-metre goal.
Lyonowever levelled shortly before the break when Vincent Enyeama parried a powerful Michel Bastos free-kick into the path of Kim Kallstrom, who tapped in.
Lille struggled to create chances after the break and Lyon scored 19 minutes into the second half when Lisandro fired past Enyeama from a fine Bastos back-pass.
