With the first leg finishing in a 2-1 defeat, Los Blancos now travel to England knowing they must score at least twice to either force extra time or win the tie outright.
They have excelled in the tournament in recent years, with manager Zinedine Zidane seeking to win the competition for a fourth time.
Here's a look at who should comprise the La Liga champions' starting XI as they seek victory in Manchester.
1. Goalkeeper and Defenders
Thibaut Courtois (GK) - The Belgian has enjoyed a fine season, keeping 21 clean sheets in 42 games. Keeping one more at the Etihad may prove difficult, but he'll be brimming with confidence.
Dani Carvajal (RB) - The right back has been superb this year, being both defensively solid and a threat going forward. A mainstay in Madrid's team, it would be a surprise for him not to start.
Raphael Varane (CB) - Having featured so prominently at the highest level for so long, it seems weird that the France centre back is only 27. As consistent as ever this year, he's been a rock at the back alongside Sergio Ramos.
Eder Militao (CB) - Used sparingly by Zidane this season, the young defender will be thrust into the spotlight in place of the suspended Ramos. Madrid will need the Brazilian to replicate the performances of the man he replaces if they are to keep City at bay.
Ferland Mendy (LB) - A tough choice between the Frenchman and the experienced Marcelo. It was Mendy, however, who got the nod regularly towards the end of the season and will likely start in Manchester.
Casemiro (DM) - Arguably the first name on the team sheet, the midfielder has unsurprisingly been excellent again this season. The Brazilian has been vital in Madrid's superb defensive shift while also threatening higher up the pitch. It'll be a tough task stifling City's midfield but he's certainly the man for the job.
Luka Modric (CM) - The veteran midfielder has impressed following the restart. Even in the twilight of his career, he continues to dominate the midfield and can still play a defence splitting pass - picking up eight assists this year.
Toni Kroos (CM) - Similarly to his midfield partner, the German has been in brilliant form of late. This game may be decided in midfield and Kroos will be hoping he can put in a dominant performance against Pep Guardiola, the man who sold him to Madrid while Bayern Munich manager.
Karim Benzema (ST) - Nailed on to start in this game, the striker has been in ruthless form this year. While his teammates have struggled to find the net, Benzema has been scoring for fun - finding the net 26 times already this season. If Madrid are to overturn the first leg result, they will be looking to their striker to come up with the goods once again.
Eden Hazard (LW) - He's had a poor season and he knows it. Featuring 16 times since his mega-move from Chelsea, Hazard has managed just one goal. Nevertheless, a strong outing against a side he's faced many times before will boost his confidence and improve his relationship with Madrid's notoriously impatient fans.
Marco Asensio (RW) - Injury kept Asensio out for almost the entirety of this season. However, the Spain international is devastating on his day and got plenty of minutes under his belt towards the end of the La Liga season.