Giampaolo Pazzini is supported by Kevin-Prince Boateng and Urby Emanuelson in a Christmas Tree formation against Anderlecht.
The Rossoneri hope to turn their season around after losing both opening home games in Serie A and again step on to the San Siro turf at 19.45 UK time for the Champions League opener.
Pazzini is the only available centre-forward, as Alexandre Pato and Robinho are injured, while Bojan Krkic and Stephan Al Sharaawy are sent to the bench.
Massimiliano Allegri opts for a Christmas Tree formation instead, fielding Emanuelson and Boateng behind the striker.
Massimo Ambrosini is benched after picking up a knock against Atalanta, replaced by Mathieu Flamini, but there are changes in defence.
Mattia De Sciglio is a surprise pick at right-back, perhaps because Ignazio Abate has fitness issues, with Philippe Mexes and Daniele Bonera in the centre.
Anderlecht are having a better domestic campaign, as they are currently third in the Jupiler League thanks to three wins and four draws.
The Belgians return to the group phase after an absence of six years. Their star player is midfielder Lucas Biglia, an Argentine of Italian descent.
Milan: Abbiati; De Sciglio, Bonera, Mexes, Antonini; Flamini, De Jong, Nocerino; Boateng, Emanuelson; Pazzini.
Milan bench: Amelia, Abate, Yepes, Constant, Ambrosini, Bojan, El Shaarawy
Anderlecht: Proto; Gillet, Wasilewski, Nuytinck, Deschacht; Bruno, Biglia, Kouyate, Kljestan; Kanu; Mbokani
Anderlecht bench: Kamiski, Safari, Juhasz, Praet, Vargas, Yakovenko, De Sutter