The Spanish club were runners-up to PSV Eindhoven in the competition's opening phase, while their illustrious visitors were taken to the final matchday before assuring a place in the knockout phase as winners of Group F.
After four successive seasons in the Champions League, Napoli returned to Europe's second-tier competition this term, as winners of the Coppa Italia, which they claimed after a penalty shoot-out win over Juventus last summer.
Having never failed to qualify from a Europa League group, the Partenopei progressed as section winners for a third time this season, recovering from an opening home defeat by AZ Alkmaar to ultimately qualify two points clear of Real Sociedad and three ahead of AZ, with whom they drew 1-1 in the return.
While Napoli are now on an unbeaten away run of seven group stage matches, they have lost their last two games outside Italy in the competition's knockout phase and will be keen to avoid a third straight defeat when they travel to ever-improving Granada this Thursday.
Following a turbulent period, in which their league form has suffered and they lost the Supercoppa Italiana to Juventus, head coach Gennaro Gattuso's position has come under much scrutiny - particularly as his current contract expires in the summer.
That intense pressure was certainly released in style at the weekend, when Gattuso was at the centre of wild on-pitch celebrations with his players, after they gained a measure of revenge against Juventus with a 1-0 league win at Stadio Diego Armando Maradona.
It was a performance of great character from the Neapolitan outfit, leaving them fifth in the Serie A standings - just two points behind fellow top-four contenders Juve. Gattuso's side can boast the second-best defensive record in Italy, while in attack, they have still managed to score at a rate of over two per game despite the ongoing absences of Dries Mertens and Victor Osimhen.
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 danger though, as they journey to a La Liga side who continue to defy expectations.
This groundbreaking Granada team earned their historic first European qualification by finishing seventh in the 2019-20 Primera Division, having been promoted only the season before.
Diego Martinez's men began the club's maiden continental voyage in the second qualifying round and once they eventually made it to the group phase, the Andalusian side made an impressive start to life in the Europa League.
Winning 2-1 at PSV, plus sealing a double over Omonia and securing two goalless draws against PAOK, enabled them to advance to the knockout rounds behind the Dutch club. With an overall record this campaign of six wins and two draws from nine European outings, they have conceded just four goals and never more than one in a game.
However, ahead of Napoli's visit to Estadio Nuevo Los Carmenes - which represents one of the biggest games in the club's history - in their last ten league and cup games, they have picked up just three wins, with three draws and four defeats during that spell.
In their latest run out, last weekend, a 2-1 home defeat to leaders Atletico Madrid was hardly an unexpected result, but hopes of a point were dashed soon after Yangel Herrera grabbed a second-half equaliser, with Angel Correa claiming the winner for Atleti less than ten minutes later. Still sitting eighth in the table though, Granada remain outsiders to qualify for another European adventure next term.
Decidedly vulnerable defensively, given 38 league goals conceded so far - only lowly Cadiz have leaked more - the Desport-owned side will need to be particularly wary of the Napoli forward line, even if it is diminished somewhat by recent injuries.
Leading the charge for Granada's own attacking department will be young Luis Suarez - an exciting Colombian talent who impressed at Real Zaragoza last year - plus venerable veterans Jorge Molina and Roberto Soldado - 38 and 35-years-old respectively. Former Valencia and Tottenham striker Soldado has scored eight goals and provided two assists this season and his experience at this level could be crucial if his current team are to extend their journey into the last-16.
Granada Europa League form: WDWWLD
Granada form (all competitions): WWDLDL
Napoli Europa League form: LWWWDD
Napoli form (all competitions): WWDLLW
Napoli coach Gennaro Gattuso - already coping without star striker Dries Mertens and having seen big-money striker Victor Osimhen only just return to the squad after illness and injury - now has in-form forward Hirving Lozano out of action. Having stepped up impressively with a number of goals and assists in recent months, the Mexican flyer has now been ruled out for a month with a hamstring injury.
Both Kalidou Koulibaly and Faouzi Ghoulam have been quarantining due to COVID-19, while fellow defenders Kostas Manolas and Elseid Hysaj are ruled out with injuries. A more regular face in the XI of late, German midfielder Diego Demme has a muscle problem and injured goalkeeper David Ospina is also set to miss out on the return to continental action.
Therefore, Gattuso's hand will be forced, with Alex Meret starting in goal, behind Amir Rrahmani and Nikola Maksimovic in central defence. Once again, Osimhen and Andrea Petagna vie for the centre-forward role.
Meanwhile, Diego Martinez is dealing with his own injury crisis at Granada, as the club's Europa League top scorer Yangel Herrera (with four), Domingos Quina, Luis Milla, Neyder Lozano and Maxime Gonalons are all potentially unavailable for this first-leg tie.
It is expected the former Osasuna boss will select a 4-2-3-1 on Thursday - despite fielding five at the back versus Atletico Madrid - with Kenedy on the right, ex-Udinese forward Darwin Machis on the left and veterans Jorge Molina and Roberto Soldado probably competing for one place up front.
Granada possible starting lineup:
Silva; Duarte, Sanchez, Duarte, Diaz; Montoro, Milla; Kenedy, Gonalons, Machis; Molina
Napoli possible starting lineup:
Meret; Di Lorenzo, Rrahmani, Maksimovic, Rui; Lobotka, Bakoyoko; Politano, Elmas, Insigne; Osimhen
We say: Granada 1-2 Napoli
Despite troubles with injuries to integral members of their defence and attack, Napoli can come away from a city, which - like their own - has a rich and diverse history, with a first-leg lead.
Boosted by a spirit-lifting triumph over old foes Juventus, the Partenopei should be capable of breaching Granada's inconsistent defence at least once and can set up a favourable platform for the return encounter next week.