Milan miss Alessio Romagnoli and rely on Carlos Bacca, while Stefano Pioli moves Gary Medel to the Inter defence in the Derby della Madonnina.
It kicks off at a packed San Siro at 19.45 GMT, follow the build-up and action on our LIVEBLOG while giving your views.
The Rossoneri have a remarkable opportunity to not only send their city rivals deeper into crisis, but also catch Roma in second place after Luciano Spalletti’s side capitulated away to Atalanta this afternoon.
Romagnoli is a huge loss for the ‘hosts’ after failing this morning’s fitness test, as he picked up a muscular problem in Tuesday’s 0-0 draw between Italy and Germany – also played at San Siro – and is not risked for a lightning fast recovery.
Instead, Gustavo Gomez gets a rare start alongside Gabriel Paletta in central defence.
Bacca is picked despite a recent goal drought, though Gianluca Lapadula will be eager to come off the bench.
Riccardo Montolivo, Andrea Bertolacci, Davide Calabria and Leonel Vangioni are injured, so 18-year-old sensation Manuel Locatelli continues to take the playmaker role.
Locatelli has already scored stunners against Sassuolo and Juventus, so is one to look at this evening.
Suso, who turned 23 yesterday, completes the trident attack with M’Baye Niang.
Inter make their debut under Pioli, having fired Frank de Boer after losing half the 14 competitive games in charge, while caretaker manager Stefano Vecchi oversaw a 2-1 defeat at Southampton and 3-0 win over Crotone.
Former Lazio boss Pioli is reunited with Antonio Candreva and the pair insist they have put past problems behind them.
Candreva and Ivan Perisic support Mauro Icardi, but the Argentine has never managed to put a goal past Milan.
The biggest changes are moving Medel to centre-back in place of Jeison Murillo, who had a nightmare for Colombia against Argentina this week, and bringing Geoffrey Kondogbia into midfield.
Medel returns after a three-match ban for lashing out in an off the ball incident, so video evidence was used against him.
Marcelo Brozovic is confident following his brace for Croatia, so he pushes Ever Banega on to the bench.
Milan: Donnarumma; Abate, Paletta, Gomez, De Sciglio; Kucka, Locatelli, Bonaventura; Suso, Bacca, Niang
Milan bench: Gabriel, Plizzari, Antonelli, Ely, Zapata, Mati Fernandez, Honda, Pasalic, Poli, Sosa, Lapadula, Luiz Adriano
Inter: Handanovic; D’Ambrosio, Miranda, Medel, Ansaldi; Brozovic, Kondogbia, Joao Mario; Candreva, Icardi, Perisic
Inter bench: Carrizo, Berni, Ranocchia, Santon, Murillo, Nagatomo, Melo, Banega, Gnoukouri, Jovetic, Biabiany, Eder, Gabriel Barbosa