The Ligue 1 attacker found the net just 10 minutes into the contest as a Jeremy Morel cross was dummied by Nabil Fekir, providing space for Lacazette to hit it first time. The blast was on point, leaving Karl Johnsson with no chance, and giving Lyon the early edge.
But Guingamp would have the last laugh as the hosts responded with a quick-fire double later in the first half.
Moustapha Diallo levelled the proceedings in the 30th minute as he slammed home a Nicolas Benezet low cross. Benezet turned receiver just four minutes later, as he headed in a Yanis Salibur cross to give Guingamp a lead they would not relinquish.
Lacazette put his side in position to find an equalizer, as he headed down a cross in the 53rd minute into a dangerous position but Maxime Gonalons was only able to knock it over the bar.
The loss leaves Lyon on fourth with 40 points, 12 points off Nice in third. Guingamp now sit eighth, but are just two points off three teams for fifth.