A pulsating 3-3 draw in the first leg at the Bernabeu leaves the tie very much up in the air, with the winner likely to be seen as the outright favourites to win Europe's top club competition.
Prior to this season City and Real have faced off 10 times in the Champions League, meeting in the group stages in 2012 and latter stages in 2016, 2020, 2022 and 2023, with the spoils generally being shared between the two giants.
With Pep Guardiola's side targeting a momentous back-to-back treble and Real Madrid chasing a record-extending 15th Champions League crown, Wednesday night's blockbuster match is all set to be another barnstormer to add to a list of titanic tussles between the two.
We've picked out three key clashes to watch out for during the second leg that could prove pivotal for either team's hopes of progression.
Rodri vs Jude Bellingham
Once an unsung hero of Guardiola's Manchester City machine, the Spanish midfield general is now seen as one of the best midfielders in Europe - if not the world - and a huge part of his side's success.
A defensive wall but elegant passer and reader of the game, not to mention a physical presence at both ends of the pitch, Rodri has now begun to add important goals to his game since netting the winner in last season's Champions League final victory over Inter.
He'll be vital for his side in a more defensive role on Wednesday night though, particularly when trying to keep Jude Bellingham quiet.
Bellingham has enjoyed a fruitful first season with Los Blancos and has already cemented himself as the main focal point going forward in an unconventional 'false-nine' style being deployed by manager Carlo Ancelotti.
His goals have spearheaded Real to the top of LaLiga, and he's also one of the top assisters in the Champions League this season.
The Englishman was kept relatively quiet in the first leg but still managed to make some darting central runs that City's defenders struggled to pick up.
Rodri will likely need to keep a watchful eye on Bellingham throughout the encounter, matching him for physicality wherever possible and providing proper cover should John Stones continue to wander forward.
Erling Haaland vs Antonio Rudiger
Erling Haaland has suffered some indifferent form in recent weeks, falling foul of a few sitters in the Premier League and facing some harsh words from TV pundits such as Sky Sports' Roy Keane, who labelled the Norwegian's general player as "that of a League Two player."
He's still popping up with goals here and there - including a penalty in City's latest 5-0 rout over Luton - but it's safe to say he's not quite hitting the mark with the same regularity as this time last year.
Haaland was also kept frustratingly quiet in the first leg against Real.
One of those reasons was simply a lack of service: City were without Belgian maestro Kevin De Bruyne, so often a laser-like finder of the tall forward and provider for his goals, but it was also down to the sturdy defensive efforts of his opponents, namely Antonio Rudiger.
The German looked comfortable in handling Haaland through the previous 90 minutes, winning his aerial duels and generally not allowing much of a sniff inside the box.
In fact, all three of City's goals were screamers from outside the area and in fairness out of Rudiger's immediate control, but he'll have otherwise been pleased by how he dealt with the English side's attacking threats, particularly through the middle.
They've had previous last season as well, so it'll be interesting to see whether Haaland becomes frustrated or can turn the tide against the fiery former Chelsea centre-back who can be prone to acts of madness.
Kyle Walker vs Vinicius Jr
Manchester City were without Kyle Walker through injury for the first leg, and it acted as a major weak spot that led to their conceding three goals in Spain.
The England right-back's pace was a major miss for Guardiola, whose side struggled to contain the pace and trickery of Real Madrid's wingers down both flanks, particularly Vinicius Jr, who picked up a brace of assists.
Walker did not feature against Luton but interestingly was on the bench, suggesting he may be fit and ready to feature against Real Madrid - a return that couldn't be more perfectly timed for the defending champions.
The pair were engaged in a riveting duel across both legs last season, with Vinicius famously attempting (and subsequently failing with) a rainbow flick against a man many regard to be one of the best wing-backs in the world.
They also embarked on a series of footraces, most of which - but not all - were won by Walker.
Vinicius is a match-winner and a man to keep quiet if City are to progress to the semi-final stage, and Walker is perhaps the best-equipped player in Europe to manage it.
