The 13-time winners made hard work of their group stage campaign but eventually qualified in first place thanks to a 2-0 win over Borussia Monchengladbach on the final matchday.
Zinedine Zidane's men head into the first leg on a four-game winning streak, and they managed to prevail 1-0 against Real Valladolid at the weekend, but Los Blancos have been decimated by injuries heading into this match.
With that in mind, Sports Mole looks at how Real Madrid could line up for the first leg in Bergamo.
Out: Rodrygo (thigh), Dani Carvajal (hamstring), Sergio Ramos (knee), Federico Valverde (muscle), Karim Benzema (ankle), Eden Hazard (muscle), Marcelo (calf), Alvaro Odriozola (muscle), Eder Militao (adductor)
Real Madrid have no fewer than nine men unavailable for the first leg through injury, and their confirmed squad list features just 12 players who can be considered first team regulars, so Zidane's hand is largely forced for Wednesday's game.
The goalkeeping spot is the one area where Los Blancos have no injury concerns, so Thibaut Courtois will continue as the last line of defence, but the rest of the backline is where their problems begin.
Lucas Vazquez will continue at right-back with Dani Carvajal and Alvaro Odriozola both out, while Sergio Ramos and Eder Miltao's absences in the heart of defence means that Raphael Varane and Nacho Fernandez will start in front of Courtois, and Ferland Mendy is a shoo-in at left-back in Marcelo's absence.
Casemiro propelled Real Madrid to victory over Valladolid but will miss the second leg if he is booked here, although Zidane has no other alternative to the Brazilian and his spot in the number 6 role is safe.
Federico Valverde is another occupant of Madrid's treatment room, so Toni Kroos and Luka Modric will man the engine room once more, meaning that Isco is likely to be the unlucky one left out of the team.
Zidane's front three also picks themselves with Karim Benzema - the tournament's fifth-highest goalscorer with 69 strikes - Rodrygo and Eden Hazard out injured, so Mariano Diaz should be supported by Marco Asensio and Vinicius Junior out wide.
Several youngsters such as Victor Chust, Antonio Blanco, Sergio Arribas and Hugo Duro will all form part of the travelling party, but Zidane is set to rely heavily on experience in this challenging fixture despite his team's mounting injury problems.