City's fourth victory out of four in Group F confirmed their progress with 12 points.
The goal was the Argentine's 178th goal for City, which takes him ahead of former record holder Eric Brook. Danilo replaced Kyle Walker in defence, while Ilkay Gundogan, Raheem Sterling and Aguero came in for David Silva, Bernardo Silva and Gabriel Jesus, who all dropped to the bench.
Sergio Aguero scored against Napoli to become Man City's all-time leading scorer. Insigne sped down the inside left flank, passing to Mertens who, with his back to goal, flicked the ball delightfully back to his onrushing teammate who then calmly curled the ball into the back of the next.
Brook scored his final goal for the club in 1939, meaning Aguero has broken a record that had stood for 78 years.
Otamendi made a nuisance of himself at the far post once more five minutes later, with the ball looping up for Stones to head against the bar.
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Everybody at City would like to congratulate Sergio and we will be celebrating this momentous Club achievement over the next few days.
15 minutes later and it was Napoli's turn to equalise as Jorginho levelled things up from the penalty spot.
But Insigne sent the crowd wild when he picked up a brilliant Mertens cross to fire past Ederson.
Referee Felix Brych pointed to the spot when City failed to clear a corner after the hour and Albiol went down under a challenge from Sane, despite contact appearing minimal.
Again, a corner proved pivotal, but this time because City sprung forward via the electric Sane on the break.