Fabio Quagliarella scored a sensational goal as Sampdoria inflicted a first loss on Carlo Ancelotti as Napoli boss.
Gregoire Defrel scored the first two goals – blasting a fantastic opening effort into the top corner from 20 yards to round off a counter-attack.
He doubled the lead with a deflected effort following a pass from Quagliarella.
Quagliarella sealed the win against his hometown club with a backheel volley from Bartosz Bereszynski’s cross.
The hosts brought on England Under-21 midfielder Ronaldo Vieira, a summer signing from Leeds, for his debut with a few minutes remaining.
Last season’s runners-up Napoli had won both their opening games under Ancelotti, who replaced new Chelsea manager Maurizio Sarri.
Elsewhere, Sassuolo beat Genoa 5-3 to keep up their unbeaten start and Luis Alberto gave Lazio – who had lost their first two matches – a 1-0 win over Frosinone.