The first leg back in February ended 2-1 to the Premier League side, but since the restart they have shown uneven form at times.
Real Madrid, by contrast, went on a 10-game win streak to claim the title in La Liga, before a draw on the last day of the season.
It promises to be the must-watch tie of the round, ahead of the last eight and beyond being held in Lisbon, Portugal.
Here’s all you need to know about the game.
When is it and what time is kick-off?
The match will begin at 8pm BST on Friday 7 August at the Etihad Stadium.
How can I watch it online and on TV?
The game will be broadcast live on BT Sport 1, BT Sport Extra 1 and BT Sport Ultimate.
Subscribers can also stream the match on the BT Sport website and app.
Manchester City are without star striker Sergio Aguero, who is injured, and left-back Benjamin Mendy, who is suspended. Pep Guardiola will have to choose between the likes of Riyad Mahrez and Phil Foden in attack, and Bernardo Silva and Ilkay Gundogan in midfield.
Real Madrid have captain and centre-back Sergio Ramos suspended, while Marcelo is a doubt with injury. Eden Hazard is expected to be fit.
Manchester City: Ederson; Walker, Fernandinho, Laporte, Cancelo; De Bruyne, Rodri, Gundogan; Mahrez, Jesus, Sterling.
Real Madrid: Courtois; Carvajal, Varane, Nacho, Mendy; Casemiro, Valverde, Kroos; Asensio, Benzema, Hazard.
Man City — 8/11
Draw — 18/5
Real Madrid — 38/11