Istanbul-based Besiktas, meanwhile, need to ideally avoid defeat to boost their hopes of beating Dinamo and Benfica to second spot.
Besiktas coach Senol Gunes "feels at home" in Naples but admits the Turkish champions face their toughest Group B encounter when they meet Napoli in the Champions League on Wednesday.
"I feel at home here, also because of the traffic coming to the stadium!" Gunes joked on Tuesday.
"Napoli are the strongest side in the group. It will be our most difficult game, but we'll try to come up with a positive result."
Successive Group B wins over Dinamo Kiev and Benfica mean Napoli stand on the verge of becoming the first team to clinch a last 16 berth after just three games.
Maurizio Sarri's men will make history if they beat Besiktas and Benfica and Dinamo draw in Lisbon, thereby securing their place in the knockout round with three games to spare.
Istanbul-based Besiktas, meanwhile, need to ideally avoid defeat to boost their hopes of beating Dinamo and Benfica to second spot in the after collecting just two points from their last two outings.
Although Napoli are without prolific Poland striker Arkadiusz Milik, after he suffered a cruciate knee ligament injury, Gunes expects Napoli to be just as strong.
Gunes added: "Milik is a very strong player, but they've got others players like (Dries) Metens who has great technique, and (Marek) Hamsik helps the attack out a lot. They have great wide players."
With Milik sidelined for several months, Manolo Gabbiadini is expected to replace the big striker flanked by either Mertens or Lorenzo Insigne and Spanish winger Jose Callejon.
There are likely to be handshakes all round at the San Paolo, as former Napoli midfielder, Swiss international Gokhan Inler, returns to the club where he spent four "great" years.
"It will be emotional for me because I spent four great years here. Once you play for Napoli, there's always a part of you that's Napolitano," said Inler, who is expected to shake off a foot problem to start.
"Playing at home, we expect Napoli to start well. They play good football so we'll have to be vigilant and focused, and try to make the difference tactically."