Rachid Ghezzal gave Lyon an early lead against Guingamp but the Parc Olympique Lyonnais was soon stunned by a Mevlut Erding equaliser.
Lyon were not to be denied however, and Alexandre Lacazette struck either side of Maxwell Cornet's effort before a late own goal from Reynald Lemaitre ensured it was a comfortable night in the end for Bruno Genesio's team.
Guingamp are now without a win in five league games and fall a place to 17th in the table.
Ousmane Dembele scored his first ever Ligue 1 brace as Rennes hammered Brittany rivals Nantes 4-1 despite being reduced to 10 men.
The 18-year-old netted in the first and last minute of the first half as Rennes ran riot.
In between those goals Kamil Grosicki kept himself onside to score past Remy Riou before Cheikh M'Bengue got the faintest of touches to Dembele's free-kick, ensuring a commanding interval advantage for the hosts.
Nantes' Adryan scored from close range on the hour to offer up some hope for his side but, despite having Giovanni Sio dismissed for a second yellow, Rennes saw the game out.
Toulouse threw away the chance to claim a surprise but vital three points in Marseille with a 1-1 draw at the Stade Velodrome. Wissam Ben Yedder put the visitors ahead but Somalia put through his own net, diverting Steven Fletcher's effort beyond Alban Lafont.
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