The first leg ended in a 1-1 draw in Spain after Kenti Robles's late strike for Los Blancos cancelled out Caroline Weir's opener just after half time.
Match preview
Gareth Taylor's side were left disappointed after their draw against Real Madrid last Tuesday, considering they allowed the home side to score deep into stoppage time at the end of the match.
However, they showed no sign of letting that affect their Women's Super League opening fixture on the weekend, when they travelled to face Everton at Goodison Park.
With key players such as Ellie Roebuck and Lucy Bronze absent through injury, a game against Everton, who have high aspirations this season, seemed to pose a difficult challenge for Manchester City.
Despite some factors being against Man City on Saturday, they ran riot in Merseyside and came away with an emphatic 4-0 victory, thanks to goals from Vicky Losada, Janine Beckie, Khadija Shaw and Steph Houghton.
Saturday's outing more than pleased manager Taylor, who said his team produced a really efficient and professional performance, which Man City will look to take into this second-leg tie against Real Madrid.
Man City have participated in the Champions League every season since their first appearance during the 2016-17 campaign, meaning that they will have an expectation of themselves to reach the group stages of the most prestigious European club competition this year.
David Aznar's Real Madrid do not come into this second leg against Man City with confidence, having lost their first league outing on Sunday.
Los Blancos travelled to face Levante at the weekend but the game got off to the worst start for the visitors, who found themselves 1-0 down inside five minutes.
Goalkeeper Maria Rodriguez saw another three goals fly past her and Real Madrid sank to a 4-0 defeat on the opening day, which meant that they could not carry over their 11-game unbeaten run that they put together in the Primera Division at the end of last season.
The two results for each of these teams in their domestic openers suggests that Man City are favourites on Wednesday, but Real Madrid will travel to England hoping to take confidence from their draw in the first leg.
Man City Women Champions League form:
Man City Women form (all competitions):
Real Madrid Women Champions League form:
Real Madrid Women form (all competitions):
Team News
Manchester City will be without injured players Roebuck, Bronze, Ellen White, and Keira Walsh, along with Georgia Stanway, who did not travel to Merseyside on the weekend as a precaution, and is unlikely to be risked on Wednesday.
Having had so many of Man City's players representing their countries at the Olympics this summer, Taylor has been left short of some options at the beginning of this campaign, so he is likely to name a similar lineup to the team which beat Everton.
That will include a starting place for number two goalkeeper Karima Benameur and another start for new signings Losada and Shaw, who will want to add to her early goal tally at her new club.
Aznar made four changes to the starting XI which started against Levante on the weekend from the team which played Man City in the first leg, but he is expected to name the same lineup which earned the draw last week.
Nahikari Garcia joined Los Blancos from Real Sociedad this summer, and she is expected to lead the line for the away side while in search of her first goal for the club.
Real Madrid will be relying on experienced centre-midfielder Aurelie Kaci to secure the middle of the pitch for the visitors, who will need to be strong defensively to keep out an in-form Man City attack.
Man City possible starting lineup:
Benameur; Stokes, Greenwood, Houghton, Morgan; Weir, Losada, Coombs; Beckie, Shaw, Raso
Real Madrid possible starting lineup:
Maria Rodriguez; Abelleira, Peter, Andres, Robles; Del Castillo, Kaci, Carmona; Gonzalez, Garcia, Lucia Rodriguez
We say: Man City 2-0 Real Madrid
Man City are expected to progress into the group stages of the Champions League, especially after their positive display against Everton on the weekend.
Real Madrid showed their defensive frailties against Levante on Sunday, and Taylor's side will be keen to exploit that and get the job done early on Wednesday.