Goals from Jeremain Lens, Dries Mertens and Antonio Marcelo lifted the Dutch side to a one-sided win as they bounced back in style from defeat to FC Dnipro in their Group F opener.
Napoli kicked off with a 4-0 win against AIK last time out as they transferred their impressive Serie A form into European competition, but Walter Mazzarri's men appeared bereft of ideas as PSV dominated.
The home side took the lead in the 19th minute as Napoli succumbed to good early pressure.
Napoli goalkeeper Antonio Rosati was called into action twice in the minutes before PSV went ahead, first saving well from Luciano Narsingh and then repelling a Mark van Bommel drive.
But he had no answer moments later when Timothy Derijck's long ball forward was collected by Lens, who fired home into the bottom-right corner.
With 35 minutes gone Rosati kept out Atiba Hutchinson's low shot from 25 yards, but four minutes before the break the hosts had their second as Mertens received the ball from Narsingh before curling home into the top corner from the edge of the area.
And Rosati was again frustrated to see his good work count for nothing when he was beaten in the 53rd minute.
The visiting goalkeeper had just produced a good stop to keep out Derijck's header but from Mertens' resulting corner Marcelo found space to nod home PSV's third.
Scenting blood and a chance boost their goal difference, PSV continued to push forward with Mertens going close on three occasions and Hutchinson again threatening, but the Napoli goal avoided further damage.