There were six additions from PSG from their win over Real Madrid in goalkeeper Keylor Navas, Thilo Kehrer, Juan Bernat, Georginio Wijnaldum, Idrissa Gueye and Neymar Junior.
However, they were given a rude awakening on four minutes when a square ball into the area from Moses Simon following a pacey counterattack allowed Kolo Muani to apply a first-time finish.
Nantes left their more illustrious opponents shell-shocked after 16 minutes and doubled their advantage through an astounding strike on the edge of the area by Quentin Merlin.
PSG continued to sit on the back-foot following the half-hour mark and watched Nantes threaten a third from a powerful close-range strike by Simon, but Navas got a firm grip.
Antoine Kombouare's charges seemed to have gone a man less minutes to halftime when Dennis Appiah picked up a red card for a foul on Kylian Mbappe, but it was cancelled following a review.
Nantes pulled further away on the stroke of halftime after Wijnaldum gave away a penalty-kick for a hand used on Jean-Charles Castelletto's header and saw Ludovic Blas execute.
PSG wasted no time to the cut arrears straight from halftime, as Neymar retrieved a through pass from Lionel Messi and fired into the net after opening an angle.
The Brazilian received a chance to grab a second from the penalty spot on 58 minutes after he had drawn a foul from Appiah in the area, but he stepped up and saw his spot-kick saved by the Nantes shot-stopper.
Moments thereafter, the Parisans decided to put on fresh set of legs as Julian Draxler entered for former Liverpool midfielder Wijnaldum.
PSG got a great chance to grab a second goal late on through Mbappe from a through pass by Draxler, but the Frenchman leaned backwards and missed, as Nantes held on for a famous win.