Separated by just one place - but eight points - in the table, the two clubs meet at the Mapei Stadium in need of maximum points to remain in the mix for European football next term.
Having had their previous scheduled outing postponed at short notice, due to a COVID-19 outbreak in opponents Torino's squad, Sassuolo have had the luxury of several extra days to prepare for the visit of the side just above them in the Serie A standings.
Currently in eighth place, but some eight points adrift of Napoli - who now occupy the last potential European spot - Roberto De Zerbi's men earned a point in their last league game, with a 1-1 draw at home to Emilian rivals Bologna - a result which extended their winless streak at the Mapei Stadium to three.
If they are to pull off a late-season comeback and claim a place in continental competition, the Neroverdi must undoubtedly improve their performance on home turf. With their last victory in Sassuolo coming back in early January, two draws - versus Parma and Bologna - and a 2-1 defeat to Spezia have since followed.
Such difficulties against the 'lesser' sides have resulted in the Emilians collecting more away points (21) than at home (14) - where they have won just three of their eleven games.
Three of that impressive away-points haul came at the expense of Napoli the last time these two clubs met in the autumn - midfielder Manuel Locatelli scoring the opener from the spot in a 2-0 win.
Now fully recovered from injury, top scorer Francesco Caputo netted again last week, making it three in a row for the experienced front man (plus four in the past five matches and 10 goals in Serie A altogether), while his chief foil Domenico Berardi - who has racked up eight goals and four assists despite a month-long absence - has been the other half of a duo which has carried Sassuolo throughout a relatively successful campaign so far.
Certainly, the Azzurri pair will be a vital part of De Zerbi's plan to claim a rare double over their Neapolitan counterparts on Wednesday.
Stalwart striker Dries Mertens helped to steer Napoli to victory upon his first start of 2021 on Sunday, scoring the opener in a 2-0 defeat of fellow Campanian club Benevento. Despite the result being somewhat soured by a late Kalidou Koulibaly red card, given for a second bookable offence, seeing off the Serie B champions provided some much-needed relief for under-pressure manager Gennaro Gattuso.
Now sitting in seventh place in the standings - though just three points adrift of the Champions League places and with a game in hand on most other sides - the Partenopei's recent inconsistency has caused concern both for their coach and his tempestuous boss, club president Aurelio De Laurentiis.
Gattuso's case for a new contract weakened further last week, as his team crashed out of European competition, 3-2 on aggregate to La Liga upstarts Granada - just a matter of days after their Coppa Italia defence came to an end at the semi-final stage.
Therefore, the very minimum required will be keeping the clubs behind them at bay - starting with a victory over Sassuolo which would put the Neapolitan outfit well clear of the chasing pack and keep pressure on the six big guns above.
Mertens, should he steer clear of further niggles, is set to spearhead the Napoli challenge in the coming weeks, with both burly strikers Victor Osimhen and Andrea Petagna currently absent through injury and Lorenzo Insigne preferring to operate from a deeper role.
A dose of the diminutive Belgian's unmistakable character and craft - aided by Matteo Politano filling in admirably for injury-stricken winger Hirving Lozano - could be just what Gattuso and company need, as the season now approaches its sharp end.
Sassuolo Serie A form: DLDLWD
Napoli Serie A form: LWLWLW
Napoli form (all competitions): LWLLWW
Napoli's list of absences stubbornly refuses to reduce in size, to the frustration of coach Gennaro Gattuso. His first-choice central defensive pairing of Kostas Manolas (injured) and Kalidou Koulibaly (suspended) will be missing again, so the rather less resilient duo of Nikola Maksimovic and Amir Rrahmani are set to fill in.
In attack, Victor Osimhen - who is currently suffering from a head injury, having previously been sidelined by a shoulder strain and then COVID-19 - Hirving Lozano and Andrea Petagna all remain unavailable.
Following his 250th Serie A appearance at the weekend - celebrated with yet another goal - Dries Mertens should start again up front, with Matteo Politano and Lorenzo Insigne in support.
Sassuolo have few injury concerns ahead of the game, with only winger Jeremie Boga and midfielder Mehdi Bourabia set to miss out, as former Napoli man Vlad Chiriches could contend for a role in the back four, having returned to full fitness.
Francesco Caputo will be at the apex of Roberto De Zerbi's customary 4-2-3-1 formation, with Domenico Berardi in close support, but several contenders remain for two further slots - including Gregoire Defrel, Hamed Traore, Filip Djuricic and Lukas Haraslin.
Sassuolo possible starting lineup:
Consigli; Muldur, Marlon, Ferrari, Rogerio; Magnanelli, Locatelli; Berardi, Traore, Djuricic; Caputo
Napoli possible starting lineup:
Meret; Di Lorenzo, Maksimovic, Rrahmani, Rui; Bakayoko, Zielinski, Ruiz; Politano, Mertens, Insigne
We say: Sassuolo 2-2 Napoli
Though Napoli are capable of ending a three-match losing streak away from home in Serie A, they may find that their hosts' attacking threat has sparked back into life - not long after it seemed like Sassuolo's hopes of a European place would be extinguished.
Considering the Partenopei's defensive selection issues, the Neroverdi can capitalise on their current frailty to claim a point, which would not bringing them any closer to the top seven but still keep the fire burning with 13 games to go.