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, after being thwarted from open play time and time again, the irate Italian did sneak home a late consolation before seeing red after the final whistle.
The fact Napoli scored at San Siro after just six minutes would have been remarkable had the real story not been their failure to score twice beforehand.
There were 45 seconds on the clock when Marek Hamsik failed to feed Higuain for an easy tap-in and moments later Valon Behrami clipped over an open goal when put through by Federico Insigne.
Milan were at sixes and sevens and, with their defence standing like statues, Raul Albiol clipped a cross into Britos for a simple headed finish.
The restart allowed Milan the chance to regroup and Balotelli tested Reina with an angled drive off his left boot before whipping the ball past a post from a free-kick.
The hosts found some more bite in the middle of the park and Valter Birsa began to cut inside from the left wing to help Balotelli and Alessandro Matri.
Another premium opportunity fell to Balotelli on the half-hour mark, but his right-footed volley flew high into the stands.
There was concern for Milan boss Massimiliano Allegri before the break as Balotelli sat down hurt in the middle of the pitch.
He was able to play on but he might, however, have preferred to stay in the changing rooms and avoid the intense frustration that followed the interval.
The second half was eight minutes old when Higuain exploded forward to shoot straight at Christian Abbiati's outstretched glove.
The light touch was not enough to keep the ball out of his goal, though, and the travelling fans roared again.
They jeered when Matri made a mess of finishing off Balotelli's clever backhee,l but hush descended in the 62nd minute when Milan were awarded a penalty for Albiol's pull on Balotelli.
The Italy striker had never before missed from the spot in 22 career attempts but saw his precious run end as Reina dived the right way to deny him.
Balotelli did not let his head drop and continued to carve out chances, forcing a solid parry from Reina before dancing on to Matri's through-ball to clatter the bar.
The battle of wills between Reina and Balotelli continued into the dying stages and the Spaniard pushed a venomous shot behind for a corner before the striker appealed - unsuccessfully - for another penalty following a tussle with Giandomenico Mesto.
He could perhaps feel vindicated when his right-footed finish beat Reina in stoppage time but his evening would end with a needless red card for dissent as Napoli celebrated a famous victory.