The Premier League leaders progress with two games to spare in Group F after making it four victories out of four at Stadio San Paolo.
As in their 2-1 victory in Manchester two weeks ago, Pep Guardiola's men were made to work hard for the points and Napoli drew first blood on this occasion thanks to Lorenzo Insigne's wonderfully crafted opener after 21 minutes.
Seemingly relieved by the Serie A table-toppers halting an assault that lasted for most of the first half hour, City centre-backs Nicolas Otamendi and John Stones converted set-piece routines either side of half-time to turn the game around.
Jorginho made it two apiece from the penalty spot in the 62nd minute but Leroy Sane, culpable for his foul on Raul Albiol, drove a counter-attack that allowed Aguero to score his 178th City goal and end Eric Brook's 79-year stay at the top of the club's scoring charts.
Napoli flagged from that point and, after substitute Bernardo Silva wasted a pair of good openings, Raheem Sterling gleefully added a fourth.
Maurizio Sarri can feel aggrieved to have taken nothing from two pulsating encounters with City and his Napoli now face a must-win clash with Shakhtar Donetsk next time out to preserve their interest in the competition.
As in the initial meeting in Manchester, events unfolded at a brisk pace from the opening whistle but it was City – smothered by the Napoli press – who found themselves on the back foot on this occasion.
The opening goal had been on the cards for some time when it arrived, with Mertens' delightful flicked return pass finding a finish to match from Insigne.
City crafted their first clear opening after the half hour when Aguero's clever lay-off to Kevin De Bruyne launched a break that ended with the Argentina striker's low effort deflecting narrowly wide.
It was another, less-likely Argentinian, who brought the Premier League leaders level in the 34th minute
De Bruyne took a quick short corner to Ilkay Gundogan and the Germany midfielder flighted an excellent left-footed cross for Otamendi to rise and nod home.
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.
City were firmly in the ascendancy by the time half-time arrived and a minute into the second half Sterling continued a menacing display by bursting through a trio of challenges before Albiol made a desperate block.
Napoli cleared the resulting corner behind but conceded from City's second attempt as Stones powered in Sane's outswinger via the underside of the crossbar.
The hosts almost spectacularly levelled in the 55th minute – Marek Hamsik denied his own moment of history when a thundering drive that would have levelled Diego Maradona's all-time Napoli scoring record cannoned back off the bar.
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.
Ederson saved a spot-kick from Mertens in Manchester but Jorginho stepped up to calmly send him the wrong way.
The City goalkeeper had no greater right to save from Jose Callejon when the defensive line in front of him disintegrated in the 68th minute but he spread himself to tip behind.
Again, a corner proved pivotal, but this time because City sprung forward via the electric Sane on the break.
Aguero collected the loose ball when the Germany winger was tackled, spied Sterling to his right but elected to go it alone and thump beyond Pepe Reina to bring up his landmark.
It was also a goal to finally crumble Napoli's resolve and they looked a beaten side before Sterling made sure on the end of a typically impeccable De Bruyne pass.