Diego Maradona was in the visiting team when Napoli last won this fixture in 1986 and South American pair Miguel Britos and Gonzalo Higuain scored the goals to stun Milan 2-1 on home turf on Sunday night.
An end-to-end game, which saw Napoli stay 100 per cent perfect with four wins from four games and join Roma in a share of first place, was most notable for the duel between the mercurial Balotelli and visiting keeper Reina.
The on-loan Liverpool man flicked Balotelli's second-half penalty wide to put paid to the striker's flawless record from the spot but the irate Italian did sneak home a late consolation before seeing red after the final whistle.
Earlier in the day, Roma got their revenge on city rivals Lazio by winning the first Derby della Capitale of the new season 2-0.
The Giallorossi lost the Coppa Italia final to their sworn enemies, in May having failed to win the derby in four previous attempts, but this time round two second-half goals from Federico Balzaretti and Adem Ljajic - the latter notching a penalty - handed the bragging rights to Rudi Garcia's men.
Any realistic hopes of a late Lazio revival at the Stadio Olimpico had been quashed when substitute Andre Dias saw red for a needless foul 10 minutes from time.
Inter Milan also continued their fine start to the season by running riot in a thumping 7-0 victory at recently-promoted Sassuolo.
The Nerazzurri never looked back after taking a seventh-minute lead through Rodrigo Palacio and were three goals to the good by half-time after Saphir Taider's effort and Raffaele Pucino's own goal.
Ricky Alvarez got on the scoresheet at the beginning of the second half, while substitute Diego Milito - on his return from injury - added a brace either side of Esteban Cambiasso's fine strike to seal an impressive rout.
Inter have now taken 10 points from their opening four league matches and are tied for second place with reigning champions Juventus - and Fiorentina.
Spanish striker Fernando Llorente scored the winner on his full Juve debut as Antonio Conte's men came from behind to beat promoted Hellas Verona 2-1.
The Bianconeri conceded an opportunistic goal from Fabrizio Cacciatore but Carlos Tevez equalised immediately.
Llorente, making his bow at the Juventus Stadium following a summer switch from Athletic Bilbao, completed the turnaround with a header deep into first-half stoppage time.
A fourth goal in as many league games from Giuseppe Rossi helped Fiorentina get back to winning ways at the expense of Atalanta.
The former Manchester United striker made up for the absence of injured strike partner Mario Gomez with the second goal in a 2-0 win at the Stadio Atleti Azzurri d'Italia. Mati Fernandez had given Fiorentina the lead before the break.
Bologna remain without a win after Alessio Cerci's penalty settled a 2-1 win for Torino at the Stadio Renato Dall'Ara.
Danilo D'Ambrosio gave the visitors the lead after two minutes but Cesare Natali equalised before being sent off for handball just before half-time. That foul allowed Cerci to step up and clinch the points for Torino.
Also without a first win are Catania and Parma, whose dull stalemate at the Stadio Angelo Massimino left both clubs languishing inside the relegation zone.