Milan, who lifted the European Cup for the seventh time by defeating Liverpool 2-1 in Athens nearly five years ago, have since been eliminated from the Champions League by Arsenal, Manchester United and Tottenham Hotspur and could only draw with Portsmouth in the group stage of the Europa League in 2009.
They now face Arsene Wenger's erratic team again, the Londoners having knocked Milan out in the last 16 in 2008.
Serie A leaders Milan welcome striker Zlatan Ibrahimovic back from a domestic ban to boost their chances after they ended a bad patch with Saturday's late 2-1 win at Italian title rivals Udinese where young forward Stephan El Shaarawy and new signing Maxi Lopez combined for the goals.
Half Italian, half Egyptian teenager El Shaarawy will probably have to miss out to accommodate Ibrahimovic despite his good form with the Swede likely to partner Robinho up front.
Coach Massimiliano Allegri has several injury problems but the treatment room is beginning to clear out with goalkeeper Christian Abbiati and centre-half Alessandro Nesta hoping to be back to face Arsenal, who have won on both of their previous Champions League visits against Milan at the San Siro.
Gennaro Gattuso and Alberto Aquilani are still injured but there is a slight chance Alexandre Pato and Kevin-Prince Boateng could make surprise returns.
Defending champions Milan top Serie A by two points but Juventus in second have two games in hand.
"It meant a lot to win at Udine, we'd just come off three defeats in five games," coach Allegri told reporters.
"That win has given us balance and serenity. This is the sprit of the guys, we have to move forward like this."
Milan, who qualified along with holders Barcelona from the group stage, have struggled in the competition since their last triumph in 2007.
Milan have also not won any of their last seven matches against English clubs and have failed to score in five of those games.
WARY WENGER
The key to Wednesday's game is what tactics Wenger employs and whether he plays safe for a draw or attempts to go for a third straight win against Milan in their own backyard.
Wenger could be wary of Milan's attacking prowess and play it cautiously but their Welsh midfielder Aaron Ramsey believes away goals could prove critical in this tie.
He told Arsenal TV Online: "If we can go there and get a few goals and then come back to the Emirates then that's going to be a fantastic result for us.
"Hopefully, we can get a couple of goals and keep them out as well."
Arsenal's fortunes have revived since French striker Thierry Henry rejoined the club on loan from New York Red Bulls, and if he does play any part on Wednesday, it is likely to be his final appeareance in an Arsenal shirt.
He is due to return to New York on Thursday after scoring three goals in six appearances to take his all-time record for Arsenal to 229
