Stefano Pioli is reportedly planning to drop Milan stars including Rafael Leao, Theo Hernandez and Fikayo Tomori for the match against Cagliari.
It kicks off at San Siro on Saturday at 19.45 UK time (18.45 GMT).
The Rossoneri are not yet mathematically guaranteed second place this season, but are practically there following the slowdown in results for both Juventus and Bologna recently.
According to Sky Sport Italia, Pioli intends to rotate the squad and sends several big players to the bench.
Leao was jeered during his most recent performance in the draw with Genoa and could be dropped along with Theo Hernandez, Tomori and Davide Calabria.
Goalkeeper Mike Maignan is not even in the squad, having been left at home due to those recurring muscular issues, so Marco Sportiello will take the gloves.
Pierre Kalulu could make his comeback after a long injury lay-off, with Samuel Chukwueze and Christian Pulisic flanking Olivier Giroud.
As for Cagliari, they are making the trip without suspended Tommaso Augello and Gianluca Gaetano, but coach Claudio Ranieri does get Nicolas Viola back.
Milan vs. Cagliari probable line-ups
Milan: Sportiello; Kalulu, Thiaw, Gabbia, Florenzi; Musah, Reijnders, Bennacer; Chukwueze, Giroud, Pulisic
Cagliari: Scuffet; Zappa, Mina, Dossena, Obert; Deiola, Sulemana; Nandez, Oristanio, Luvumbo; Shomurodov