In the teams' first-ever Champions League meeting, Milan will aim to emulate their four-goal victory in Naples earlier this month, while their visitors - surely soon to succeed the Rossoneri as Italian champions - seek to continue some scintillating form in Europe's top club competition.
Match preview
Though the defence of their Scudetto has not gone entirely to plan, as Wednesday's opponents have streaked clear at the top of the table, Milan have still managed to navigate their way to the Champions League quarter-finals for the first time since 2012.
On that occasion, the Lombardy giants were eliminated by Pep Guardiola's Barcelona; they last reached the semis some five years earlier, when they went on to lift European football's grandest prize for the seventh time.
Ahead of their first leg contest this week, the Rossoneri preserved their place in Italy's top four with a grim goalless draw at home to Empoli last Friday - a far cry from their previous outing, when they summoned up the form and fortitude of last year's run to the title by beating an unusually shaky Napoli side 4-0 at Stadio Maradona.
Despite landing such a psychological blow, the 22-point chasm currently separating them from the Serie A summit means securing a place in next season's Champions League via their league finish is now the sole domestic focus for Stefano Pioli's side, who have already exited the Coppa Italia.
While they have often lacked fluency, as Rafael Leao's post-World Cup travails continue and Pioli's paper-thin squad too often fails to rise to the occasion, Milan have proved particularly tough to beat in Europe: including a gritty stalemate at Tottenham in the last 16, which secured a slim 1-0 aggregate win, the Group E runners-up have kept clean sheets in each of their last four Champions League fixtures.
Before visiting Naples next week for the return leg, Milan will want to continue that trend against the 2022-23 edition's top scorers, and a glance at the history books suggests they can: the Rossoneri have lost only one of nine previous all-Italian match-ups in continental competition.
Famed for their superstition, Neapolitans will prefer to focus on the fact that Milan have won just three of their 16 most recent Champions League knockout matches, failing to score in 10.
Perhaps more pertinently, the second-city side have managed to defeat their southern rivals only once in the clubs' last nine meetings at San Siro. Indeed, Napoli have won on each of their last three trips to the fabled Stadio Giuseppe Meazza - including a 2-1 league victory there earlier this season.
That success was just one of 24 from 29 Serie A fixtures so far - the latest arriving in Lecce last weekend - and not only are preparations well under way for the city's first Scudetto party for over 30 years, Luciano Spalletti's side still have their eyes on breaking more new ground in Europe.
In addition to a series of spectacular wins making them the Champions League's leading scorers on 25 goals - their average of 3.1 per game is the fifth-best ever in a single campaign - Napoli have been rock-solid at the back, as a 5-0 aggregate scoreline against last-16 victims Eintracht Frankfurt would suggest.
Without the totemic presence of star striker Victor Osimhen, though - due to an injury sustained on Nigeria duty - they stumbled badly when meeting Milan at Stadio Maradona two weeks ago.
If the baton was supposed to be passed from one Italian champion to another on that occasion, the Partenopei clearly fumbled it, but as they seek to stay on track for the Champions League final in Istanbul, Wednesday's encounter is arguably when it will matter more.
AC Milan Champions League form:
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AC Milan form (all competitions):
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Napoli Champions League form:
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Napoli form (all competitions):
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Team News
After making several changes to his starting XI against Empoli, Stefano Pioli was again made acutely aware of his squad's lack of strength-in-depth, so Milan's regulars should all return on Wednesday evening.
Rafael Leao and Olivier Giroud will be back from the start, with Simon Kjaer and Rade Krunic likely to join them. Brahim Diaz also returns, in hope of replicating his superb performance against Napoli earlier this month.
Pierre Kalulu is expected to miss out with a calf problem, though, which leaves wily veteran Kjaer to tussle with young Malick Thiaw for the right to partner Fikayo Tomori at the heart of the hosts' back four.
While Giroud is Milan's top Champions League scorer this term with four goals, Napoli have four men on the same tally as the French forward: Victor Osimhen, Piotr Zielinski, Giovanni Simeone and Giacomo Raspadori.
However, in addition to the bitter blow of losing Serie A's Capocanonniere leader Osimhen to a thigh injury, his deputy Simeone is now a doubt after picking up a knock against Lecce.
Unless the Argentina international can recover in time for the trip to Italy's second city, Raspadori may have to deputise in the visitors' front three, on the left of which will be 'Kvaradona' himself - Khvicha Kvaratskhelia.
AC Milan possible starting lineup:
Maignan; Calabria, Tomori, Kjaer, Hernandez; Tonali, Krunic, Bennacer; Diaz, Leao; Giroud
Napoli possible starting lineup:
Meret; Di Lorenzo, Kim, Rrahmani, Rui; Anguissa, Lobotka, Zielinski; Lozano, Raspadori, Kvaratskhelia