The Azzurri are seeking a first Scudetto for more than 30 years, and paused for the World Cup eight points clear at the top of the table following 11 league wins on the spin. Inter, meanwhile, have stumbled several times on the road and are some 11 points adrift of their southern rivals.
Match preview
Desperate to finally end their title drought, which dates back to the days of the late, great Diego Maradona, Napoli ended 2022 by winning each of their last 11 Serie A matches - the best streak in the Italian top flight since a typically dominant run from Juventus five years ago.
Finishing up the first phase of their campaign by beating Atalanta, Empoli and then Udinese - the latter via a 3-2 victory at Stadio Maradona in November - Luciano Spalletti's side lead the standings by eight points from Milan ahead of their first fixture of the new year, but must now build that momentum all over again.
During a long mid-winter break, the Neapolitans were in friendly action on several occasions - following wins over Antalyaspor and Crystal Palace with defeats to Villarreal and Lille - and the goals continued to flow for a prolific front line.
Former Inter boss Spalletti now takes his side to the second city, at the helm of the only team still undefeated throughout Europe's top five leagues, and he will hope they can retain such status despite meeting both the Nerazzurri and Juve in their first three matches of 2023.
Within touching distance of also being crowned Campione d'Inverno (winter champions) by leading at Serie A's halfway stage, Napoli will meet Eintracht Frankfurt in February, as they seek to continue a so-far scintillating Champions League campaign, in which stars such as Khvicha Kvaratskhelia and Victor Osimhen have shone brightly.
Before now and then, though, the Partenopei have work to attend to domestically, and they first must end a losing streak against Inter at San Siro; they have been beaten on each of their last four visits to Milan's football cathedral, after limiting their losses to two in the previous seven.
Inter tuned up for their return to competitive action with a training camp in Malta, followed by four friendly wins from five and a 1-1 draw against Real Betis during the World Cup break, but they now start part two of their Serie A campaign with one of its toughest tests yet.
Defensive deficiencies away from home have been at the root of the Nerazzurri's pre-Christmas slip down the standings - four losses and 18 goals conceded on the road attest to that - and they kick off 2023 down in fifth spot.
Therefore, their most immediate concern is getting a grip on a top-four place, as they aim for a return to the Champions League - a competition from which they eliminated Barcelona and will meet Porto in the last 16 next month.
For all their woes outside of Milan, Simone Inzaghi's squad - who have sometimes toiled without the injured Romelu Lukaku leading their attack - still managed to win six from seven at home in Serie A before Calcio's top tier came to a halt.
They often make a fast start, too, having scored the most goals in the first 15 minutes of play this season, and throughout 2022, no team netted at least three times in more home games than Inter - only Napoli matched their tally of eight.
Now aiming to pick up where they left off after edging out Atalanta 3-2 in their final fixture of last year, the Coppa Italia holders know victory is vital if they are to retain any realistic Scudetto dreams, so the stakes could hardly be higher.
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Napoli Serie A form:
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Team News
While World Cup winner Lautaro Martinez has finally returned to training after his nation's triumph in the final and subsequent celebrations, Simone Inzaghi is set to favour Romelu Lukaku - who endured a rather less fruitful time in Qatar - and reliable veteran Edin Dzeko up front on Wednesday.
Croatia midfielder Marcelo Brozovic has suffered a calf strain which could keep him out of action until Inter's Supercoppa Italiana clash with city rivals Milan later this month, so Henrikh Mkhitaryan should feature from the start, having overcome a back injury picked up in the recent friendly against Sassuolo.
Francesco Acerbi is set to be preferred to Stefan de Vrij in the hosts' back three, while Andre Onana takes the gloves ahead of club captain and long-term number one Samir Handanovic, having left the Cameroon camp in controversial circumstances last month.
They will primarily aim to keep Serie A's nine-goal top scorer Victor Osimhen at bay, but Napoli have already racked up 37 goals in the league this term through a variety of different sources. Chief among them is winger Khvicha Kvaratskhelia, who returns from a back problem which sidelined him before the break.
Regular centre-back Amir Rrahmani is also available again and battles it out with ex-Inter man Juan Jesus to partner Kim Min-jae at the heart of the visitors' defence.
Hirving Lozano and Matteo Politano resume their tussle for a spot on the right flank too, but Mario Rui should beat Mathias Olivera to a start at left-back.
Inter Milan possible starting lineup:
Onana; Skriniar, Acerbi, Bastoni; Dumfries, Barella, Calhanoglu, Mkhitaryan, Dimarco; Dzeko, Lukaku
Napoli possible starting lineup:
Meret; Di Lorenzo, Kim, Jesus, Rui; Anguissa, Lobotka, Zielinski; Politano, Osimhen, Kvaratskhelia