The European giants put on a thriller in the first leg in Manchester last week.
City claimed a stunning 4-3 victory with Bernardo Silva scoring the eventual winner.
But Karim Benzema's double - including his outrageous panenka penalty at the Etihad - has given Real plenty of reason for optimism at home.
Both sides are in good form ahead of their second-leg clash with City smashing Leeds in the Premier League over the weekend.
Meanwhile, Real beat Espanyol to clinch La Liga glory.
The winner of this tie will then take on Liverpool or Villarreal in the Champions League final in Paris on May 28.
Real Madrid v Man City: talkSPORT commentary
This Champions League clash will take place on Wednesday, May 4.
talkSPORT will have full coverage from the Santiago Bernabeu with kick-off set for 8pm.
Adrian Durham will be your host while commentary will come from Jim Proudfoot and Andy Townsend.
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Real Madrid v Man City: Team news
Kyle Walker took part in training ahead of City's semi-final trip to Madrid but John Stones was not involved.
Walker has been absent for the last five matches while recovering from an ankle issue.
Fellow defender Stones was forced off in the first half of the first leg against Real last week and subsequently missed Saturday's 4-0 Premier League win at Leeds.
"Kyle trained today [Tuesday] and he will travel," Pep Guardiola said.
"We will decide ahead of the game - he is three weeks without training but we are happy he is back.
"Joao Cancelo is no doubt. He is really good. We will see with Kyle how he is after treatment. Then we will decide."
Real Madrid v Man City: What has been said?
Pep Guardiola feels City will probably have to improve on their first leg performance against Real to progress to the Champions League final.
He said: "Yes, probably we will have to be better.
"But at the same time I would like to tell you one thing - we could play much, much worse than we played and we could win, and not anyone can deny my assessment is right.
"So nobody knows, football is unpredictable. Sometimes you get something you don't deserve, sometimes you don't get something maybe you deserve, for the effort, for many things."
Real Madrid v Man City: Match stats
Real Madrid have lost their last two UEFA Champions League matches and have only lost three in a row once before, doing so between February and October 2020, a run which included two defeats to Man City. Current manager Carlo Ancelotti has never lost three matches in a row in the Champions League, with this match his 178th in the competition.
Should Manchester City qualify for the UEFA Champions League final, they will have done so in consecutive seasons, having lost 1-0 to Chelsea in last season's final. They'll be the fourth English side to reach consecutive European Cup/Champions League finals, after Liverpool (1977/1978, 1984/1985, 2018/2019), Manchester United (2008/2009) and Nottingham Forest (1979/1980).
Real Madrid have been eliminated in all five previous UEFA Champions League semi-finals when they've lost the first leg; however, they have progressed from two of their last three knockout ties when losing the first leg, in the 2015-16 quarter-final vs VfL Wolfsburg and this season's Last 16 vs Paris Saint-Germain.
Manchester City have progressed in nine of the previous 10 UEFA Champions League two-legged knockout ties when they've won the first leg, only failing in the Last 16 vs Monaco (5-3 first leg, 1-3 second leg).
Manchester City have won their last three UEFA Champions League matches against Real Madrid; only two sides have ever won four in a row against them in European competition, with Ajax doing so between 1973 and 1995 and Bayern Munich between 2000 and 2002.
The first leg between Manchester City and Real Madrid was only the second semi-final first leg in UEFA Champions League history to see seven goals scored, along with Liverpool 5-2 Roma in 2017-18. Only two semi-finals have seen 10 or more goals scored over the two legs: Juventus 6-4 Monaco in 1997-98 and Liverpool 7-6 Roma in 2017-18.
Real Madrid's Karim Benzema has scored nine UEFA Champions League goals in the knockout stages this season, with only Cristiano Ronaldo in 2016-17 (10) ever scoring more in a single season. Benzema could become the fourth player to score in both legs of the quarter-final and semi-final in a season, after Fernando Morientes (2003-04, Monaco), Neymar (2014-15, Barcelona) and Edin Dzeko (2017-18, Roma).
Man City's Pep Guardiola has won four UEFA Champions League matches against Real Madrid, with only Ottmar Hitzfeld winning more (7). Two of his wins over Madrid have come at the Bernabeu (2011 with Barcelona, 2020 with Man City) and he could become the first manager to win three away from home there.
Kevin De Bruyne has 18 UEFA Champions League assists for Manchester City, the most of any player and behind only Neymar (25) and Kylian Mbappé (20) in the competition since his debut for City in September 2015. De Bruyne scored and assisted in the first leg, one of only two occasions he's done so in the UEFA Champions League - the other was at the Bernabéu vs Real Madrid in February 2020.
Real Madrid's Vinícius Júnior has created 28 chances in open play in the UEFA Champions League this season, the most by a player since Dusan Tadic in 2018-19 (36) and most by a Los Blancos player since 2010-11 (Mesut Özil, 32). He has also has six open play assists, including four at the Bernabéu: since 2003-04, the only player with more than six in a season is James Milner in 2017-18 for Liverpool (7).