Reigning Premier League champions City head into the match on the back of successive domestic wins, while Madrid have relinquished control at the top of La Liga in recent weeks.
City were rocked by UEFA's announcement on February 14 that they have been expelled from European football competitions for the next two seasons for breaching Financial Fair Play regulations. The Citizens have pleaded their innocence and have vowed to take the case to the Court of Arbitration for Sport.
As things stand, though, the club will not have another chance to crack the Champions League until 2022-23, by which point a number of key players - and indeed boss Pep Guardiola - will likely have moved on.
That will no doubt provide some added motivation as City fly out to the Spanish capital for the opening 90 minutes of a tie which, as Madrid striker Karim Benzema put it, is expected to be very tight.
Guardiola's men have got their league campaign back on track with wins over West Ham United and Leicester City over the past week. All that has done, though, is ensure they will almost certainly not finish any higher or lower than second place.
The only way this campaign can now be considered a success is to go all the way on the continent, which they have been unable to come close to achieving in any of their eight previous seasons in the competition.
There is also the small matter of next weekend's EFL Cup final showdown with Aston Villa, of course, as well as an FA Cup last-16 tie with Sheffield Wednesday, but the Champions League now takes priority over all other competitions for Guardiola.
The English champions could have done with an easier first knockout-round fixture, then, with Madrid very much the "kings of the competition" in the words of Guardiola.
Three-in-a-row winners between 2016 and 2018, Los Blancos were stunned by surprise package Ajax at this stage last season and are now out to make amends.
Whereas City cruised through their group by taking 14 point from the 18 on offer, Madrid lost heavily at Paris Saint-Germain and drew the reverse fixture, either side of being held at home by Club Brugge.
Zinedine Zidane's men have also been far from convincing domestically, with their Copa del Rey campaign being ended by Real Sociedad earlier this month and their lead at the top of La Liga completely evaporating.
Crashing out of the Champions League stage in the first knockout round for a second season running will be pretty disastrous for Madrid, even more so if their underwhelming form continues domestically.
However, Zidane has won all 12 Champions League ties he has been involved in as Madrid manager and currently holds three Champions League trophies as a head coach, a joint-record alongside Bob Paisley and Carlo Ancelotti.
The Frenchman, who returned to the Santiago Bernabeu after Madrid's loss to Ajax last season, has become a specialist at winning European Cups.
Guardiola has now gone nine years since the second and most recent of his continental triumphs, meanwhile, and he recently admitted that he will be considered a failure if his time at the Etihad Stadium ends without him lifting the famous trophy.
That adds an extra edge to a tie that many will hope lives up to the hype. At the end of the second leg, it will either be Zidane or Guardiola left picking up the pieces of a season that has fallen apart.
Real Madrid's Champions League form: LDWWDW
Real Madrid's form (all competitions): WWLWDL
Manchester City's Champions League form: WWWDDW
Manchester City's form (all competitions): WWLLWW
Marco Asensio is Madrid's only other absentee, with the Spaniard yet to play a single minute this term after suffering a serious knee injury during pre-season.
Zidane has a decision to make on whether to recall Gareth Bale, who has struggled to hold down a place in the side this term and missed out against Levante at the weekend due to a sickness bug.
Raheem Sterling is also pushing for inclusion after recovering from a hamstring injury that has kept him out of the Citizens' last two matches.
Leroy Sane has been closing in on a return to first-team action, but this match is expected to come too soon for his comeback.
Real Madrid possible starting lineup:
Courtois; Carvajal, Varane, Ramos, Mendy; Valverde, Casemiro, Kroos; Bale, Benzema, Isco
Manchester City possible starting lineup:
Ederson; Walker, Fernandinho, Laporte, Mendy; De Bruyne, Rodrigo, Bernardo; Mahrez, Aguero, Sterling
Head To Head
City have failed to beat Madrid in their four previous meetings, each coming in the Champions League, including two losses at the Santiago Bernabeu.
Los Blancos have prevailed in their last four Champions League knockout ties against English opposition, meanwhile, most recently beating Liverpool 3-1 in the 2018 final.
The Citizens have been knocked out in each of their three previous two-legged ties against Spanish clubs, with their semi-final loss to Madrid four years ago still fresh in the memory.
We say: Real Madrid 1-0 Manchester City
Madrid have scored in each of their last 22 home games in the knockout stages of the Champions League. Even when out of form the Spanish giants seem to find a way in Europe, and we expect them to take a slender advantage with them to the Etihad Stadium for the return tie on March 17.