The player that City covet so much did the damage for Walter Mazzarri's side with goals in the 18th and 49th minutes - either side of Mario Balotelli's simple finish - to send the Azzurri to second spot on the Group A table.
It was City's second loss in their past 19 in all competitions (after nine straight wins) as Napoli notched up just their second victory in their last eight which puts them in a position where they can get points from bottom-of-the-group Villarreal in the final match to advance to the next phase.
City made a composed beginning but Napoli soon kicked into gear and had a number of chances before taking the lead in the 18th minute when Ezequiel Lavezzi swung a corner in from the left which was met by a slight Edinson Cavani header. The ball went past Yaya Toure and was missed by Aleksandar Kolarov to sneak in at the front post past Joe Hart.
Man City worked their way back into proceedings and managed a leveler in the 33rd minute in similarly poor defensive circumstances as Napoli's opener. Salvatore Aronica's brittle clearance fell straight to David Silva who struck firmly from an angle with the home side's goalkeeper Morgan De Sanctis pushing it straight into the path of a waiting Mario Balotelli who tapped home for his tenth goal in his last nine outings.
Early in the second half, Napoli were back on top when Cavani netted his fourth Champions League goal in five matches with a well-taken side-footed volley from Andrea Dossena's cross from the left as the Stadio Sao Paolo crowd broke out into full voice.
The match lulled for a spell before City began to press forward in search of a leveler but it never came and the visitors were probably lucky not to go further behind when Christian Maggio sent a ball into the area from the right in the 64th minute to see Hart knock it away with an outstretched hand as Lavezzi slipped at a crucial stage when he could have been on his feet for a tap-in.
Five minutes later, Hart kept City in the match when he came up with a top save from Lavezzi's shot from an angle after he had received Marek Hamsik's clever ball and went past Vincent Kompany who slipped on the edge of the area.
In the 76th minute, Hamsik managed to get around Kolarov after receiving Cavani's pinpoint cross field pass before advancing into the area but his goalbound attempt clattered into the near upright moments before Napoli keeper De Sanctis made a vital reflex save to deny Balotelli's close range half-volley.
The contest was heating up late and Hart again came up with the goods when Maggio got free from Kolarov in the City area but he could only knock the through-ball from Lavezzi straight at the England gloveman who was having a huge match.
Balotelli saw his 82nd minute header go wide of the mark before his volley was safely held by De Sanctis who also kept out substitute Sergio Aguero as the Naples outfit put qualification in their own hands with Bayern Munich already through after tonight's 3-2 win over Villarreal.