The Premier League giants are the favourites to advance to the final eight courtesy of their 2-1 victory in the first leg at the Bernabeu back in February.
City have already claimed a trophy this season in the shape of the EFL Cup, but they were knocked out in the semi-finals of the FA Cup by Arsenal and gave up their Premier League title to Liverpool.
Here, Sports Mole looks at how Pep Guardiola's side could line up when they take to the field against the reigning La Liga champions.
City will again be without the services of Sergio Aguero due to a knee problem, while Benjamin Mendy is suspended due to the booking that he picked up at the Bernabeu in the first leg.
Guardiola has plenty of decisions to make when it comes to team selection, and there is a chance that Fernandinho could revert to the spot alongside Aymeric Laporte in central defence, with Eric Garcia dropping to the bench.
Joao Cancelo started at left-back against Norwich City last time out and that could again be the case here, while Rodri and Ilkay Gundogan are likely to join Kevin De Bruyne as part of a midfield three.
Phil Foden and Bernardo Silva are both pushing to be involved on the opposite side, but it seems likely that Riyad Mahrez will get the nod, having been handed a start in the first leg at the Bernabeu.