Milan rely on Ante Rebic, Brahim Diaz and Sandro Tonali amid injury problems, while Fiorentina revamp again with Franck Ribery, Jose Callejon and Dusan Vlahovic.
It kicks off at 14.00 GMT, follow all the build-up and action as it happens on the LIVEBLOG.
The Rossoneri are not only top of the Serie A table, but with Sassuolo losing and Juventus drawing, they have the opportunity to go five points clear.
Coach Stefano Pioli is still out of action with COVID, along with his assistant manager, so Daniele Bonera is again on the touchline.
There are injury problems too, as Zlatan Ibrahimovic, Rafael Leao, Samu Castillejo and Ismael Bennacer are on the treatment table.
It means after Thursday’s 1-1 Europa League draw at Lille that Ante Rebic again leads the way – against his former club too – but this time Brahim Diaz gets the nod with Hakan Calhanoglu and returning Alexis Saelemaekers.
Tonali takes over from Bennacer in midfield alongside Franck Kessie.
Fiorentina are in crisis and new coach Cesare Prandelli lost his opener at home to Benevento in another dire performance.
He has practically a full squad to choose from and starts Callejon with Ribery and Vlahovic in a 4-3-3 formation, while ex-Milan men Giacomo Bonaventura and Patrick Cutrone are on the San Siro bench.
Milan: G Donnarumma; Calabria, Kjaer, Romagnoli, Theo Hernandez; Tonali, Kessie; Saelemaekers, Calhanoglu, Brahim Diaz; Rebic
Milan bench: A Donnarumma, Tatarusanu, Conti, Dalot, Duarte, Gabbia, Kalulu, Hauge, Krunic, Colombo, Maldini
Fiorentina: Dragowski; Milenkovic, Caceres, Pezzella, Biraghi; Pulgar, Castrovilli, Amrabat; Callejon, Vlahovic, Ribery
Fiorentina bench: Terracciano; Barreca, Igor, Lirola, Martinez Quarta; Bonaventura, Duncan, Eysseric, Saponara, Borja Valero, Cutrone, Kouamé