The Argentine genius overtook Eric Brook as the Citizens' leading scorer in the 69th minute, reaching 178 goals in City blue since his 2011 move from Atlético Madrid.
However, it was Napoli who dominated proceedings early on with City struggling to get out of their own half as Maurizio Sarri's side pressed relentlessly.
But City, who had only trailed for seven minutes all season, were level just 13 minutes later when Leroy Sané‘s short corner was met by Nicolás Otamendi who headed home his first Champions League goal.
And, three minutes into the second half, City repeated the trick with Sané again whipping the ball in from a short corner and John Stones crashing a header off the underside of the bar and down onto the line – his third goal of the campaign already.
But Napoli still presented a threat and equalised just after the hour when Sané was adjudged to have tripped Raul Albiol in the penalty area at the corner. Midfielder Jorginho took the spot kick for Napoli and converted.
Agüero restored City's lead seven minutes later with Sané again key, charging into the hosts' half before laying the ball off for City's No.10 to fire past Pepe Reina from just inside the box.
And City wrapped the points up, becoming the first English team to win in Naples at the same time, when Raheem Sterling slid the ball home following another swift counter-attack in injury time.
But how was the game won and lost? We break down the match and look at the tactical battles which brought City a hugely impressive win in Southern Italy.
As expected the match did not lack for entertainment. There was no quarter asked and no quarter given. Having rested key players in Napoli's first three Champions League group games in order to focus on his side's Serie A title assault, Sarri put out the strongest side he could and Napoli went for it.
After 20 minutes the hosts had dominated the ball – with 60 per cent possession to City's 40 – and tested Ederson on three occasions. The Premier League leaders, meanwhile, had barely been able to get out their third of the field.
It was high-intensity stuff with Napoli pressing City tirelessly and forcing Pep Guardiola's men to really work for their openings to try to get up the field. But City are build to play like that. They remained calm and patient and gradually grew into the game, ending the first half in control.
And when City pressed the hosts they were just as aggressive, to the point that holding midfielder Fernandinho frequently found himself so far forward he was in nosebleed territory as the visitors tried to turn the ball over.
Ghoulam underlines his quality
Napoli were on top for a breathless first half an hour with everything good from the Partenopei coming down their left-hand side.
The duel threat of Liverpool transfer target Faouzi Ghoulam and goalscorer Insigne was too much for City to handle and with Danilo over-worked and over-stretched at right-back time and time again.
City had well and truly been warned and it all came to a head when the former Real Madrid man was caught on the hop for Napoli's opener. Insigne played a mesmerising one-two with Mertens and burst into the penalty area to slot past Ederson.
But some of the sting was taken out of Napoli's left-hand side when Ghoulam was replaced with what appeared to be a hamstring injury after half an hour.
The flying Algerian's departure not only disrupted the hosts but forced Sarri to switch Elseid Hysaj to the left-back spot with veteran right-back Christian Maggio on in Ghoulam's place.
Pep pinpoints Napoli's weakness
Guardiola is known for and characterised by his meticulous preparation. We know that he will spend days in advance of matches watching his team's opponents, discovering their weaknesses and devising a plan to take advantage.
And he did the same again in Naples as City twice scored from corners at the Stadio San Paolo. The Partenopei lead Serie A but they have shipped four goals from set pieces this season – only Sassuolo and Cagliari, with five, have let in more.
In order to maximise City's chances of a good delivery the corners were almost all taken short. And the ploy worked to a tee. City's first, the equaliser, came when a short corner was delivered for Otamendi to nod home his first Champions League goal.
And the visitors repeated the trick in the second half with Stones benefitting from another precise delivery from Leroy Sané.
Sané steps up to the plate, again
The momentum of the game shifted in Manchester City's favour when Napoli lost the impressive Ghoulam to injury after half an hour and not just because they were unable to double up on Danilo when attacking.
Once a flying wing-back in Walter Mazzarri's Napoli side which reached the Champions League last 16, Maggio looked every one of his 35 years and showed why he is now just a squad player in the twilight of his career.
Sané got in behind on multiple occasions and wreaked havoc down the left.
In the same way that City had been troubled by the hosts' constant attacks on the opposite flank in the first half, the Premier League side caused mayhem with their livewire German charging at Maggio relentlessly. It was little surprise, therefore, to see Sané steam past the former Italy cap in the build-up to Agüero's goal.
The German international was eased into life at the Etihad last summer following his switch from Schalke. But he is yet another example of Pep knowing best and has come of age this season in spectacular fashion, already bettering last season's Premier League goal tally.