With a place in the Champions League final at stake, the Calcio giants will battle it out for a first-leg advantage ahead of next week's decider at the same iconic venue.
Match preview
Showcasing this year's Italian renaissance in Europe, a Milan derby double now decides one of the teams to progress from the Champions League semi-finals.
The winner then takes their place in the showpiece finale early next month - holders Real Madrid or English champions Manchester City will await in Istanbul.
Two of five Serie A sides still standing in continental competition, Milan and Inter play out a fourth Derby della Madonnina of the season this week, with both teams recording one league victory apiece - the Rossoneri were 3-2 winners back in September, while the Nerazzurri edged February's contest 1-0, and they also came out on top in the Supercoppa Italiana.
Milan, who deposed Inter as Italian champions last year but have since been toppled from their throne by their Champions League quarter-final victims Napoli, were runners-up in Group E during the autumn; improving on a group-stage exit in 2021, which came after a seven-year absence from the competition.
The seven-times European champions then eliminated Tottenham Hotspur in the last 16 before frustrating a faltering Napoli side last month; winning 2-1 on aggregate against their Scudetto successors.
Reflecting their resilience throughout the knockout stages so far, Stefano Pioli's side conceded only once across those four games - Victor Osimhen's late strike at Stadio Maradona, when the tie had essentially been decided - and they are likely to take a similar approach against Inter.
Milan's most recent Champions League triumph came back in 2007 - when they earned a slice of revenge against Liverpool following the clubs' epic clash in Istanbul two years earlier - and en route to their previous victory in 2003, they overcame their city rivals at the last-eight stage.
On that occasion, the Rossoneri were ultimately awarded the tie due to crowd trouble, having also won a semi-final contest between the pair two years beforehand: then, a 1-1 aggregate result curiously saw them progress on 'away' goals, despite both games taking place at San Siro.
Given a subsequent rule change, that will not be an issue this time around, as Pioli's men aim to shake off some stuttering Serie A form and sweep past their old foes once again.
While Milan have continued dropping points domestically and now trail Inter by two in the league standings, Simone Inzaghi's side are finally running into top form and will kick off Wednesday's first leg on the back of a five-match winning run.
Since a pulsating 3-3 draw with Benfica that sealed passage into the Champions League semi-finals, they have brushed aside Empoli, Lazio, Verona and Roma by scoring 14 times and conceding just once, in addition to Derby d'Italia victory over Juventus in the Coppa Italia.
That surge does not entirely mask the Nerazzurri's struggle for consistency in Serie A this season. Beaten by several Calcio minnows, they have lost 11 times already and are still to secure a top-four finish - and with it a return to Europe's premier club competition.
However, their prowess in cup competitions cannot be doubted. As well as reaching the Coppa Italia final, where they meet Fiorentina later this month, Inter qualified from a tough Champions League group also featuring Bayern Munich and Barcelona, eliminating the latter to set up a last-16 clash with Porto.
As well as defeating the Portuguese champions in that tie and then knocking out Benfica in the quarter-finals, in 2023 they have overcome Napoli, Milan (twice, including January's Supercoppa triumph) and now both Rome clubs following a 2-0 win against Roma last weekend.
Like their semi-final opponents, Inter have kept three clean sheets from four knockout-round games so far, with ex-Ajax goalkeeper Andre Onana playing a similarly important role to that of Mike Maignan for Milan.
The three-time European champions' last success at this exalted level came back in 2010, under Jose Mourinho, but in the course of the next few weeks, Inzaghi aims to add the ultimate prize to two Supercoppas and a Coppa Italia he has lifted since succeeding Antonio Conte.
AC Milan Champions League form:
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AC Milan form (all competitions):
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Inter Milan Champions League form:
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Inter Milan form (all competitions):
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Team News
After stumbling against Cremonese a few days earlier, Milan selected a more conventional starting XI for their 2-0 win over Lazio at the weekend, with Olivier Giroud, Theo Hernandez and Sandro Tonali all returning to the side.
However, Rafael Leao's game was ended early in the first half due to a muscular injury and Alexis Saelemaekers came on in his place, causing concern about his readiness for Wednesday. If the Portuguese forward is unable to recover, Saelemaekers could deputise again, rather than Ante Rebic being recalled.
Only Tommaso Pobega and Zlatan Ibrahimovic are set to miss out due to injury - the latter is not registered for the Champions League in any case - so the only other change made by Stefano Pioli may be Brahim Diaz replacing Junior Messias on the right flank of a familiar 4-2-3-1 formation.
Inter, meanwhile, initially left Lautaro Martinez, Edin Dzeko and Henrikh Mkhitaryan on the bench in Saturday's game at Stadio Olimpico, but all three could return to the starting lineup in midweek.
A recently revived Romelu Lukaku will have other ideas, though, as Simone Inzaghi has seen signs of life in the Belgian's once-prosperous pairing with Martinez of late. Dzeko would therefore stay sidelined if the famed 'Lu-La' partnership is reunited.
Soon to exit San Siro for Paris, Milan Skriniar joins Robin Gosens in missing out due to injury, but Danilo D'Ambrosio could return to the squad after overcoming a muscular problem.
AC Milan possible starting lineup:
Maignan; Calabria, Tomori, Kjaer, Hernandez; Tonali, Krunic; Diaz, Bennacer, Saelemaekers; Giroud
Inter Milan possible starting lineup:
Onana; Darmian, Acerbi, Bastoni; Dumfries, Barella, Brozovic, Mkhitaryan, Dimarco; Martinez, Lukaku
We say: AC Milan 0-1 Inter Milan
Sure to be a tightly-contested affair, with so much at stake and both teams practising safety-first football, it could be just one goal which separates the sides after the tie's first 90 minutes.