The capital side, who would have clinched their eighth title by avoiding defeat, had Juan Bernat sent off before the break after the Spaniard had cancelled out Thomas Meunier's early own goal.
Lille's Jose Fonte and teammates celebrate after the match.
But Bernat was later sent off to a red card and combined with Meunier and Thiago Silva going off injured early on, proved a recipe for disaster as Lille scored four times in the second-half to come away with an easy win.
The game got off to an eventful start with Kylian Mbappe having two goals disallowed for offside in the first 15 minutes and PSG losing Thiago Silva to a muscle injury two weeks before the French Cup final against Stade Rennes.
The defeat delayed their Ligue 1 title celebrations by another week.
"We're going to be champions but we can not lose like this".
PSG needed four minutes to respond as Mbappe controlled a bouncing ball and floated over a looping cross for Bernat to finish.
"Putting five past PSG doesn't happen to everyone, even if they did only have 10 men, but we played well tonight", Pepe told Canal+.
"We can't lack personality like that, and concede three, four, five goals".
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Christophe Galtier's side went 2-1 up six minutes into the second half when Pepe beat the offside trap to score from close range.
PSG boss Thomas Tuchel called the heavy loss "normal" before complaining about the lack of healthy players at his disposal.
PSG played the match with a number of notable absentees, including Neymar, Edinson Cavani and Angel Di Maria.
"They didn't have any chance in the first half, and there was Kehrer's opportunity in the beginning of second half". We might go there with 13 players.
"Given the circumstances, we had a good game, I have to protect my players At 10, it became extra hard", Tuchel said.
Qatari owner Nasser Al-Khelaifi could also be heard saying: "We need to raise the level of French football!"
"Yes, I will be telling the president as this situation is not good".
Saint-Etienne reclaimed fourth spot in the French top flight after cruising to a 3-0 win over Bordeaux.