Milan completely revamp into a 3-5-2 formation with Divock Origi partnering Olivier Giroud and Rafael Leao on the bench, while Inter have Hakan Calhanoglu, Lautaro Martinez and Edin Dzeko.
It kicks off at the Stadio Giuseppe Meazza – in the San Siro area of Milan – at 19.45 GMT.
You can follow all the build-up and action as it happens from today’s Serie A games on the LIVEBLOG.
The Rossoneri are in crisis after terrible results including the 3-0 defeat to Inter in the Supercoppa Italiana last month in Riyadh, going out of the Coppa Italia to 10-man Torino, plus back-to-back Serie A defeats with Lazio and Sassuolo in which they conceded nine goals.
Stefano Pioli said he had to make radical changes and he stood by his word, dropping Rafael Leao for the second game in a row.
He also transforms their 4-2-3-1 tactics to a 3-5-2, with Matteo Gabbia in defence, Junior Messias in central midfield and a front two of Origi and Giroud.
Ismael Bennacer, Fikayo Tomori, Mike Maignan, Zlatan Ibrahimovic and Alessandro Florenzi are all out of action.
Inter have a full squad to choose from, with Marcelo Brozovic available on the bench after his World Cup exploits for Croatia, but Calhanoglu retains the midfield spot against his old club.
Dzeko also staves off competition from Romelu Lukaku to partner Lautaro Martinez, although Joaquin Correa is out with a slight muscular issue.
Milan Skriniar starts, but is no longer the captain after announcing his desire to join PSG as a free agent.
Inter: Onana; Skriniar, Acerbi, Bastoni; Darmian, Barella, Calhanoglu, Mkhitaryan, Dimarco; Lautaro Martinez, Dzeko
Milan: Tatarusanu; Kalulu, Kjaer, Gabbia; Calabria, Messias, Tonali, Krunic, Theo Hernandez; Giroud, Origi