Lacazette opened the scoring but Guingamp scored two goals in the first seven minutes of the second period.
Lyon's alarming slump in form continued on Saturday as they lost 3-1 at home to Guingamp despite leading scorer Alexandre Lacazette putting them in front at their Parc OL.
Lacazette opened the scoring with his seventh league goal of the campaign from the penalty spot but Guingamp turned the game on its head with two goals in the first seven minutes of the second period from Yannis Salibur and Marcus Coco.
Coco added another to complete the turnaround and condemn Lyon to a fifth defeat in their last six games in all competitions.
Remarkably, it was the first time in 35 years that they had lost a league game at home after leading at half-time.
It was also a fifth loss in 10 Ligue 1 outings for Bruno Genesio's side, who remain 10 points adrift of leaders Nice before they go to Metz on Sunday. Guingamp are fifth.
Such a poor start to the campaign for Lyon had not been contemplated after their outstanding run towards the end of last season, and the pressure is now very much on Genesio.
"It's a big blow and hugely disappointing because we've lost at home for the second time this season," lamented Genesio.
"We put in two completely different displays, a first half that was fairly good, and another where we totally lost our way. That's typical of a team in a difficult situation and one that doubts itself."
Lyon took the lead in the 37th minute when Lacazette -- who missed a penalty in the 1-0 midweek Champions League loss to Juventus -- netted from the spot after Maxime Gonalons had been fouled in the area.
It was a first league goal since August for Lacazette.
However, Lyon contributed to their own downfall with some awful defending in the second half.
Guingamp equalised when Jimmy Briand robbed youngster Mouctar Diakhaby in the area and set up Salibur, who fired home.
The Breton side were in front in the 52nd minute as Lyon cheaply gave the ball away in their own half and Briand was again the provider, squaring for Coco, who had an easy finish.
Lyon were denied a penalty when Lacazette went down in the box under a Jordan Ikoko challenge, and substitute Mathieu Valbuena was stretchered off in tears after falling awkwardly only minutes after coming on.
Club president Jean-Michel Aulas later told Canal Plus Sport that Valbuena, capped 52 times by France, had a dislocated shoulder and would require an operation.
The home side's misery was compounded as Guingamp struck again in the 77th minute, France under-21 international winger Coco dispossessing Rafael before running through to blast a shot past Anthony Lopes.
The final whistle was met by loud jeers from the Lyon support.
Monaco went second after destroying Montpellier 6-2 on Friday, with Radamel Falcao getting the principality club's first goal from the penalty spot on his return after a month on the sidelines.
Paris Saint-Germain, in third, entertain Marseille in the Classique on Sunday in what will be Rudi Garcia's first match as coach of the visitors.
Toulouse can leapfrog the champions into third if they win at Angers later on Saturday.