The first chance came inside two minutes, falling the way of Napoli striker Lorenzo Lucca - leading the line in the absence of the injured Rasmus Hojlund - but he dragged his shot wide.
At the other end, it was Vanja Milinkovic-Savic who was forced into the first save of the night, getting down well to palm Dennis Man’s shot behind following the Romanian’s neat one-two with Ismael Saibari.
From the resulting corner, Guus Til nodded over from Joey Veerman’s delivery, with Ryan Flamingo the next player to go reasonably close from a Veerman set-piece, heading into the side-netting.
After a period when Napoli had been under the cosh, Lucca would have been ruing a loose touch from a Scott McTominay pass that dribbled its way into Matej Kovar’s gloves, before Leonardo Spinazzola tried his luck from range.
Napoli did get their noses in front just after the half-hour mark, however, as Spinazzola fizzed in a cross which was headed in emphatically by McTominay.
Antonio Conte would have been hoping that his side would take charge at this point, but instead, PSV drew level when a sustained spell of possession culminated in Ivan Perisic crossing for Alessandro Buongiorno to accidentally turn past his own keeper.
And Napoli barely had time to compose themselves before they were 2-1 down as Saibari tucked home from close range following a rapid breakaway which owed much to Perisic's tenacity and awareness, although the visitors protested for a penalty after a challenge by Jerdy Schouten on Lucca in the build-up.
Lucca was again the talking point after half-time when he headed off target from Matteo Politano’s inviting corner.
Saibari, tail up, then almost punished Billy Gilmour’s weak header back to Milinkovic-Savic, but it wasn’t long before PSV doubled their advantage.
Mauro Junior shimmied past Buongiorno, sending him to the ground, before the Brazilian’s cutback was put through Sam Beukema’s legs and in by Man.
A triple change duly followed from Conte, with former PSV attacker Noa Lang the most attacking of the introductions in place of Gilmour, but things could have got even worse for Napoli when Andre-Frank Zambo Anguissa’s underhit pass almost led to Til making it four.
After Lucca was bizarrely sent off for dissent, though, the fourth did arrive for Peter Bosz’s men, courtesy of a blistering drive by Man, before another McTominay header brought the smallest hope of a revival.
PSV quashed that belief in double-quick time, however, as first, substitute Ricardo Pepi made an instant impact off the bench, tapping in at the back post, and then a bewitching passing move was finished off in thumping fashion by Couhaib Driouech to send the Philips Stadion crowd wild.
PSV are now on four points in the league phase, one more than Napoli, who have lost successive games for the first time since last December after suffering a 1-0 defeat to Torino at the weekend.
Flashscore Man of the Match: Mauro Junior (PSV)