Charles De Ketelaere, Rafael Leao and Olivier Giroud take on Lautaro Martinez, Joaquin Correa and Hakan Calhanoglu in the fiery Derby della Madonnina.
It kicks off at San Siro at 17.00 UK time (16.00 GMT).
These city rivals tussled to the last day of the season for the Scudetto, with Milan emerging triumphant for the first time in 11 years, while Inter lifted the Coppa Italia and Supercoppa Italiana.
Both have injury problems going into the clash, as Alessandro Florenzi, Rade Krunic, Ante Rebic and Zlatan Ibrahimovic are out.
De Ketelaere is the only summer signing in the starting XI for the Rossoneri, with Leao, Giroud and Junior Messias.
Inter cannot play Romelu Lukaku due to a muscular injury, but Alessandro Bastoni does shake off flu symptoms to start in defence.
Tucu Correa and Calhanoglu are in support, with Matteo Darmian rather than Robin Gosens, benching Edin Dzeko.
Milan: Maignan; Calabria, Kalulu, Tomori, Theo Hernandez; Bennacer, Tonali; Messias, De Ketelaere, Leao; Giroud
Inter: Handanovic; Skriniar, De Vrij, Bastoni; Dumfries, Barella, Brozovic, Calhanoglu, Darmian; Lautaro Martinez, Correa