Fekir, who is reportedly attracting interest from a host of Premier League clubs, scored his 18th goal of the season in only the second minute at the Groupama Stadium.
The France international whipped a stunning effort around the one-man wall which bemused PSG goalkeeper Alphonse Areola before crashing into the net.
PSG equalised through left-back Layvin Kurzawa on the stroke of half-time, but the visitors were reduced to 10 men in the 57th minute when Dani Alves picked up a straight red card.
Lyon took full advantage when former Manchester United winger Depay – who has been on the fringes of Lyon's first team – came off the bench to score a spectacular winner.
In the final minute of a fiery contest, the Dutchman cut in from the left and arrowed his venomous effort straight into the top corner.
Not a bad way to condemn PSG to only their second league defeat of the season.
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