Lyon, who had already qualified for the next phase, finish second behind Fiorentina, who snatched a late 2-1 win over Liverpool at Anfield. Third-placed Liverpool continue in the Europa League while Hungarian champions Debrecen finished last with six defeats in as many games.
Striker Bafetimbi Gomis opened the scoring on 25 minutes, following up after Debrecen keeper Djordje Pantic failed to block an effort by Sidney Govou.
Brazilian midfielder Michel Bastos doubled the advantage from close range just before the break. Miralem Pjanic made it 3-0 on the hour from a Bastos cross before defender Aly Cissokho wrapped up the scoring with a powerful shot from the edge of the box.
"We owed this to our fans," Cissokho told reporters after Lyon scored their first win at their Gerland stadium since a 2-1 Ligue 1 victory over Toulouse in September.
"Of course we would have preferred to win the group because playing the (last 16) return leg at home is an advantage, but never mind,"
Lyon, who had gone six matches without victory in all competitions, looked sluggish at first and the first chance went to the visitors with a distant low angled shot from Peter Czvitkovics that France keeper Hugo Lloris did well to save.
Jeered by their fans, the home side reacted after that and midfielder Jean Makoun hit the back of the net five minutes later but was ruled offside.
The seven-times French champions did not look that comfortable after moving ahead and Debrecen had another opportunity with a deflected effort by striker Adamo Coulibaly just before Lyon made it 2-0.
The match was more one-sided after that and the boos from the Gerland stands gradually stopped.
Lloris and Coulibaly both finished the game with bandages after sustaining face cuts in a clash of heads. The Lyon keeper's injury looked superficial, however, and he should be fit to face champions Girondins Bordeaux in Ligue 1 on Sunday.
"This is just what we needed to boost our confidence before facing Bordeaux," Cissokho said.
