The La Liga outfit continue to make waves in their impressive debut continental campaign and are now intent on finishing the job at Stadio Diego Armando Maradona, to claim a place in Friday's last-16 draw.
While Napoli extended their unbeaten away run to seven group stage matches before the turn of the year, they have now lost their last three games outside Italy in the Europa League knockout phase, after the Serie A side were turned over by ever-improving Granada last Thursday night in Andalusia.
Ahead of a loss which came as a result of two early goals, the Partenopei could name just 12 senior outfield players, with the game coming between major Serie A encounters with Juventus - which they won against the odds due to a brilliant display of unity - and Atalanta, who they were beaten by after an incredible six-goal second half in Bergamo.
As in Granada, the Neapolitans went behind first at the Gewiss Stadium - something which they have done a total of 13 times this term, but failed to salvage even a point on 10 occasions - suggesting a certain lack of composure and perhaps even character in the camp.
Following a turbulent period in which their league form has suffered and they lost the Supercoppa Italiana to old rivals Juve, head coach Gennaro Gattuso's position has come under much scrutiny - particularly as his current contract expires in the summer.
Napoli's proud defensive record, having been the second-best in Serie A, was torn to shreds during the 4-2 defeat on Sunday, and it now seems that the victory over Juventus was only a brief calm episode amid choppy waters for the Partenopei, as in their last five games they have registered only one victory to four defeats.
Injuries have undoubtedly played their part in these recent travails and it is expected that Gattuso's list of unavailable players will still number eight this Thursday, presenting the under-fire manager with another selection headache as he bids to keep his team in contention for the last piece of silverware available to them this season.
One of six former UEFA Cup winners in the final 32 – along with Ajax, Bayer Leverkusen, PSV, Shakhtar Donetsk and Tottenham Hotspur - it would cap the club's regeneration over the past decade if Napoli could claim a first European title since the heady days when Diego Maradona bestrode the stadium which now bears his name.
The next step on that path is fraught with difficulty though, as they host a Spanish side who continue to defy expectations and hold a clear psychological edge from last week.
On domestic duty, Napoli have managed to maintain a goalscoring rate of over two per game - despite key forwards Dries Mertens and Victor Osimhen missing vast chunks of the campaign through injury and illness - so they must believe that a memorable comeback remains possible.
A surprise package whose ambition just keeps growing, Granada head to Campania seeking to defend their 2-0 lead and earn a place in the last-16 draw - representing a phenomenal achievement for a side which languished in Spain's second tier just two years ago.
There was little doubt as to the star of the show last week, as midfielder Yangel Herrera was influential throughout. The 23-year-old Venezuelan scored Granada's opener and out-performed Napoli's more established star names, earning the one-time Manchester City trainee glowing praise from the Spanish sports press.
Led by the youngest manager in La Liga, Diego Martinez, Granada have surpassed all expectations in the last three seasons, winning promotion to the top flight in their first campaign under the 40-year-old, then qualifying for Europe with a seventh-placed finish in 2019-20. Making their continental debut this term, they comfortably navigated the group stage and now have one foot in the final 16.
Ahead of the trip to Naples, the plucky Andalusian outfit are undefeated in UEFA competition outside Spain, having won their first four away fixtures this season, before drawing the fifth 0-0 with PAOK in Greece. Furthermore, they have conceded just twice on their European travels to date.
Though Granada were beaten 3-2 at bottom club Huesca last weekend, despite taking an early lead through Domingos Quina, they remain in the top half of the Primera Division standings. Nonetheless, Martinez will have concerns over their recent form, as in their last six games in all competitions, they have picked up just one win, with two draws and three defeats coming during that spell.
Certainly, their defence is not exactly invulnerable, as they have now conceded 41 goals in La Liga - the worst defensive record in the league. Keeping the back door shut on Thursday will, though, be integral to Granada's hopes of continuing a memorable maiden voyage through unprecedented waters for the club.
Napoli Europa League form: WWWDDL
Napoli form (all competitions): DLLWLL
Granada Europa League form: DWWLDW
Granada form (all competitions): DLDLWL
Napoli forward Victor Osimhen spent the night under observation at a Bergamo hospital following an alarming collapse towards the end of the defeat to Atalanta on Sunday. The Nigeria international was knocked unconscious in an incident during the final minutes of the game and then stretchered off the pitch, so will join the lengthy list of absences for the home side.
Mostly first-choice options, Dries Mertens, Diego Demme, Andrea Petagna, Elseid Hysaj, David Ospina, Kostas Manolas and arguably this season's star man, Hirving Lozano, all miss out this week. Therefore, Gennaro Gattuso will be forced to field almost the same team as on Sunday, only with Osimhen being replaced by the rather more diminutive Lorenzo Insigne, who will operate as a 'false nine'.
Granada boss Diego Martinez is set to retain the 4-2-3-1 employed in the first leg, with Yangel Herrera and Maxime Gonalons expected to come back into the starting lineup in midfield.
Defender German Sanchez - sent off in the disappointing defeat to Huesca - Antonio Puertas, Yan Eteki and Alberto Soro are all expected to drop out of the side, as Darwin Machis, Jose Molina and Kenedy return in attack.
Napoli possible starting lineup:
Meret; Di Lorenzo, Maksimovic, Koulibaly, Rui; Elmas, Bakayoko, Ruiz; Politano, Insigne, Zielinski
Granada possible starting lineup:
Silva; Foulquier, Duarte, Sanchez, Neva; Herrera, Gonalons; Kenedy, Montoro, Machis; Molina
We say: Napoli 2-1 Granada
The dream could be set to continue for modest Granada, as their more illustrious opponents continue to struggle with both injuries and expectations.
Napoli's only hope of overturning their deficit will be if they can somehow summon the spirit and cohesion shown against Juventus earlier this month. Expect the Partenopei to hit the net at least once, due to the opposition's obvious defensive deficiencies, but their makeshift side may come up just short without 12th-man support from the Stadio Maradona faithful.