City, though, were not to be outdone and re-took the lead in the 69 minute when a solo run from Sergio Aguero saw him dribble his way into the box before firing into the roof of the net, 3-2.
Napoli started the better of the two teams and created the first significant chance on goal in the 13 minute when Dries Mertens broke through on goal, but he was thwarted by the City keeper.
Manchester City's Nicolas Otamendi, back to camera, celebrates with teammates after scoring tonight.
The Citizens edged out Napoli 2-1 in the reverse group stage game at the Etihad and are now looking to do the double over Maurizio Sarri's men. John Stones rose highest to meet Leroy Sane's cross and power a header past Pepe Reina to make it 2-1.
Napoli came close to levelling in the 56th minute when Insigne struck a powerful effort from distance, but the Italian's effort smashed off the crossbar during a strong spell for the home side.
Yet after Jorginho had equalised with a penalty just after the hour, Aguero's predatory instincts ensured City were not to be denied in their bid to become the first English team to win a European match in Napoli's forbidding San Paolo Stadium.