For all their continental success in recent years, Zinedine Zidane's side currently find themselves outside of the top two in Group B, with Borussia Monchengladbach and Shakhtar Donetsk on course to make the knockout stages over Real and Inter at the midway point, but something has to give when the top two sides meet this week.
Los Blancos did not warm up for this crucial game in optimal fashion as Villarreal took a point from their meeting with Zidane's men in a 1-1 draw at the weekend, with a Gerard Moreno penalty cancelling out Mariano Diaz's early opener in La Liga.
Here, Sports Mole looks at how Real Madrid could line up for their visit to San Siro on Wednesday evening.
Real Madrid's injury concerns are far from ideal before facing the potent attacking duo of Lautaro Martinez and Romelu Lukaku, with Zidane already confirmed to be without stalwart Sergio Ramos as well as Karim Benzema and Federico Valverde with injuries, while Luka Jovic is recovering from coronavirus.
With journeyman Benzema once again ruled out of Real's game, Mariano Diaz will keep his place at the forefront of Zidane's attack for the trip to San Siro.
Further boosts for Zidane would be the returns of Brazilian duo Casemiro and Eder Militao from positive coronavirus tests, and the former could lineup alongside Toni Kroos in midfield while Militao is in line to replace Nacho Fernandez in defence, with Raphael Varane's inclusion all but guaranteed.
It remains to be seen whether Zidane will revert back to the 4-3-3 or opt for a 4-2-3-1 for the trip to San Siro, but a victory in this game could see Real march to the top of the standings in Group B depending on the outcome of Monchengladbach's clash with Shakhtar, so Zidane should set his side up to attack.
However, that formation leaves questions asked as to who will occupy the number 10 role. Martin Odegaard has enjoyed plenty of game time in La Liga, while Isco is still waiting for his first taste of Champions League action this season, but the Spaniard has plenty of experience on the big stage and he should get the nod if Zidane lines up in a 4-2-3-1.
Eden Hazard and Marco Asensio are likely to line up either side of the Spaniard, although Rodrygo is pushing for a start after his winner saw Real Madrid take the spoils last time out against Inter, but both he and fellow Brazilian Vinicius Junior will likely be watching on from the bench at the start of this one.