The Serie A side, who beat Dynamo Kiev 2-1 in their opener, raced ahead with goals by Marek Hamsik, Arkadiusz Milik and a Dries Mertens double.
They lost focus towards the end and allowed the Portuguese visitors to get some consolation with goals by Goncalo Guedes and Eduardo Salvio.
"We have shown that we are up to taking part in this competition," Napoli coach Maurizio Sarri told a news conference. "Beating a top team like this isn't easy".
Napoli have six points from two games in Group B, four more than second-placed Besiktas.
On Tuesday Juventus pounded Dinamo Zagreb 4-0 away from home to go joint top of Group H with four points from two games. (Ansa)