The European champions are level on points with defending title-holders Barcelona after five games of the season, but take on a Sevilla side in good goalscoring form at a ground where they have struggled in recent years.
It has been a mixed bag for Sevilla so far this season, but the past week has shown how quickly momentum can shift in football.
Pablo Machin's side had won just one of their opening four La Liga games heading into their first Europa League group outing of the season, including drawing blanks in back-to-back domestic defeats.
However, fast forward 10 days and Sevilla will host Real Madrid having scored 11 goals in their last two games - five of which have come from Wissam Ben Yedder alone.
The striker scored a brace as Sevilla took Standard Liege apart with a 5-1 win in Europe last week, and he backed that up with a first-half hat-trick in his side's remarkable 6-2 away win at Levante on Sunday.
In truth, it should not have taken Machin's men so long to get up to speed; Wednesday's match will be their 14th of the campaign following their participation in the Europa League qualifying rounds and their Spanish Super Cup defeat to Barcelona.
Sunday's victory has lifted them back up to seventh place, though - where they finished last season and only one point off the Champions League spots.
The nature of that rout at Levante also means that only Barcelona and Real Madrid have scored more than them this season, with Sevilla scoring more last weekend alone than last season's runners-up Atletico Madrid have managed from their five games so far.
Of course, Real Madrid will provide a much sterner test than either of Sevilla's last two opponents, but it was only four months ago that the Andalusian outfit beat the same opponents at this stadium as they ended the season with three successive home league wins.
Sevilla are winless and goalless in the league in front of their own fans so far this term, though, and their recent 2-0 defeat at the hands of Getafe means that they are facing the possibility of losing back-to-back league games at the Pizjuan for the first time in more than three years.
Recent La Liga form: WDLLW
Recent form (all competitions): DWLLWW
After a summer of so much change at Real Madrid, with Zinedine Zidane and Cristiano Ronaldo both leaving, it will have settled a lot of nerves that new boss Julen Lopetegui has made such a promising start.
Los Blancos have not always been at their best so far in 2018-19 - as typified by the scrappy, VAR-reviewed goal which saw them scrape past Espanyol at the Bernabeu on Saturday - but they have so far got the job done.
Last weekend's win leaves Madrid level on points with Barcelona at the top of La Liga, with both Clasico rivals having dropped just two points from their opening five league games.
After keeping just one clean sheet in their first five outings under Lopetegui across all competitions, Madrid now appear to have tightened things up at the back too, holding their opponents at bay during last week's Champions League win over Roma and then again against Espanyol.
Madrid have not kept three clean sheets on the bounce since November 2017, although it is worth noting that the previous two have both come at home. Los Blancos have surprisingly not managed an away clean sheet in La Liga since March.
Indeed, Madrid have also only won one of their last five league outings on the road - a run which includes a 3-2 defeat at this very stadium in their penultimate game of last season.
There is a fine balance for Lopetegui to strike heading into this difficult game as he considers rotation, with a Madrid derby against Atletico to come on Saturday and a Champions League trip to Moscow three days later.
A number of his players have also travelled to and from London to attend FIFA's The Best awards this week, where Raphael Varane, Sergio Ramos, Marcelo and Luka Modric were all named in the Team of the Year, while the latter was also named The Best Men's Player for 2018 to break the 10-year dominance of Ronaldo and Lionel Messi.
Whether Lopetegui risks resting some of those players remains to be seen, although the fact that Barcelona take on bottom-of-the-table Leganes could have an impact on his decision as he looks to keep pace with the reigning champions.
Recent La Liga form: WWWDW
Recent form (all competitions): WWWDWW
Lopetegui rested Gareth Bale for the weekend win over Espanyol, so the Welsh winger - who has four goals already this season - should return for this match.
Marcelo was also given the night off and could return, although Lopetegui could look to rest either Ramos or Varane after both played the full 90 minutes.
The newly-crowned best player in the world is also likely to be included from the off, although Lucas Vazquez is available should Lopetegui opt to rest the Croatian.
As for Sevilla, Ben Yedder's goalscoring exploits over the past week make him a shoo-in for a starting role alongside Andre Silva, who has four goals in five games since joining the club.
Daniel Carrico marked his first league appearance of the season with a goal at Levante and that could be enough for him to keep his place in the side too.
Indeed, with no new injury concerns, manager Machin could be tempted to name an unchanged team to the one which hit Levante for six.
Sevilla possible starting lineup:
Vaclik; Gomez, Kjaer, Carrico; Navas, F Vazquez, Banega, Sarabia, Vidal; Ben Yedder, Silva
Real Madrid possible starting lineup:
Courtois; Odriozola, Nacho, Ramos, Marcelo; Modric, Casemiro, Ceballos; Bale, Benzema, Asensio
Head To Head
Goals have been the order of the day in recent meetings between these two sides, with 89 in the past 19 clashes - an average of more than 4.5 per game.
Madrid were 5-0 winners when these two sides met at the Bernabeu in December, but the most recent meeting saw Sevilla triumph 3-2, with Madrid's goals both coming in the final five minutes.
Indeed, Los Blancos are winless in their last four visits to this stadium across all competitions, including three successive La Liga defeats.
We say: Sevilla 2-2 Real Madrid
Real Madrid will be slight favourites for this match, but with the possibility of rotation coupled with Sevilla's goalscoring form over the past two games, the hosts will be confident of getting something out of this one.