The Reds reunite with their 2005 and 2007 final foes on the back of a dampening 1-0 loss to Nottingham Forest in the Premier League, Slot's first competitive defeat as Liverpool manager.
The Dutchman has made two changes to the side that started the clash with the Tricky Trees, bringing in defender Kostas Tsimikas and attacker Cody Gakpo to seemingly freshen up the left-hand side.
Gakpo will take the place of Luis Diaz as Diogo Jota continues in the final third, while Tsimikas's unexpected promotion to the starting lineup means that Andrew Robertson drops down to the bench.
Slot has otherwise kept faith with the same side from the defeat to Forest, as Mohamed Salah and Dominik Szoboszlai continue in the attack, with potential debutant Federico Chiesa among the substitutes alongside Darwin Nunez.
Tammy Abraham dropped in one of three Milan changes
Ryan Gravenberch and Alexis Mac Allister both hold their places in the engine room too, despite the presence of Curtis Jones and Wataru Endo, while Ibrahima Konate keeps Jarell Quansah at bay in defence.
Meanwhile, Milan head coach Paulo Fonseca - also taking charge of his first Champions League match for the Rossoneri - has made three alterations to the side from their 4-0 Serie A thrashing of Venezia at the weekend.
Tammy Abraham won one penalty and scored another in that victory, but the ex-Chelsea man is among the players to lose their spot in the starting lineup, as Alvaro Morata comes back in to lead the line.
The Euro 2024 winner will join forces with Christian Pulisic and the ever-dangerous Rafael Leao in the final third, while a familiar face in Ruben Loftus-Cheek starts in a three-man midfield.
Fonseca's other two changes come in defence, as Fikayo Tomori is back in for Matteo Gabbia, while captain Davide Calabria - who missed the weekend's win with a knock - replaces Emerson Royal at right-back.
AC Milan: Maignan; Calabria, Tomori, Pavlovic, Hernandez; Reijnders, Fofana, Loftus-Cheek; Pulisic, Morata, Leao
Subs: Nava, Torriani, Okafor, Zeroli, Chukwueze, Emerson, Bartesaghi, Terracciano, Musah, Gabbia, Abraham
Liverpool: Alisson; Alexander-Arnold, Konate, Van Dijk, Tsimikas; Gravenberch, Mac Allister; Salah, Szoboszlai, Gakpo; Jota
Subs: Kelleher, Jaros, Gomez, Endo, Diaz, Nunez, Chiesa, Jones, Robertson, Quansah, Morton, Bradley