Their opening European clash is at San Siro on Tuesday evening, when Sandro Tonali will return as an opponent for the first time since his €80m summer move to Tyneside.
Pioli had until now been reticent to make adjustments to his line-up, but was forced into changing the defence against Inter when Fikayo Tomori was suspended and Pierre Kalulu injured.
Tomori is available again and should start against Newcastle, although Sky Sport Italia suggest some other tweaks from the coach too.
Samuel Chukwueze was snapped up from Villarreal for €28m including bonuses and could get his first start in the Milan jersey, therefore sending Christian Pulisic to the bench.
There might also be a switch in midfield, as one of Ruben Loftus-Cheek, Rade Krunic and Tijjani Reijnders might be rested after playing non-stop so far this season.
Krunic is the favourite to make way for Yunus Musah.
Milan (probable): Maignan; Calabria, Tomori, Thiaw, Theo Hernandez; Loftus-Cheek, Musah, Reijnders; Chukwueze, Giroud, Rafael Leao