The Italian side travel to England as underdogs in a Group A that also features Bayern Munich and Villarreal but coach Walter Mazzarri refused to be daunted and said Napoli could draw much encouragement from their Europa League outings last season.
"I will tell my players not to focus too much on the other side and how strong they are," Mazzarri told a news conference on Tuesday. "Statistically we are the least favourite in this group, but I do not think that is very important.
"All we need to do is keep focused, keep calm and think about the competition one game at a time. Tomorrow we will play Manchester City and we will play it as if it were a final, after we have done our best we will see where we are at."
Napoli, who last appeared in European Cup competition 21 years ago, only returned to Serie A four season ago and have rapidly grown into title contenders despite modest means.
Manchester City, meanwhile, have invested hundreds of millions of pounds on players in the past three years, prompting reporters to ask Mazzarri whether he felt like it was a bit of a David and Goliath contest.
"It's either us being very clever for the approach that we have or the other side being a little bit foolish because if we manage to do what we are doing in the way that we do it then people can see it does pay off," Mazzarri said.
"It's only a matter of getting in the right mindset and looking after and nurturing our group of players. Last year Manchester City finished third in the Premier League and so did Napoli in Serie A so we can see the results were there."
The Italian side got a taste of life on the big stage by playing a friendly against European champions Barcelona last month and despite losing 5-0, it was valuable experience.
"It was quite useful to have a feel of the atmosphere, to take in the environment," Mazzarri said.
"We possibly had too much reverence for the other team, so in a way we were surprised Barcelona chose us for a friendly. But more important than game in Barcelona was our very convincing performance in the Europa League."
Napoli reached the round of 32 in the continent's second tier competition last season, losing to Villarreal. City were also in the Europa League last term, falling at the last-16 stage.
