The Turkish champions know that they will more than likely slip out of an automatic qualification spot should they lose in the Spanish capital
Ronaldo returned from inspiring Portugal to World Cup qualification with his 25th club goal of an already remarkable season on Saturday, setting Los Blancos on their way to a 5-0 La Liga win at Almeria.
However, the Ballon d'Or hopeful hobbled out of that victory early in the second half and Madrid confirmed on Monday that scans showed he had suffered a "lesion in the posterior part of the left thigh".
It is unclear exactly how long Ronaldo will be sidelined for, but the fact he is almost certain to miss Wednesday's clash at the Bernabeu bodes well for Galatasaray.
The Turkish champions were on the receiving end of a Ronaldo hat-trick during their 6-1 drubbing in the reverse fixture on matchday one, while the forward also scored three times across two legs as Madrid prevailed in last season's quarter-final between the two sides.
Scoring contributions in each of his side's four Champions League matches this term means that Ronaldo has already matched the record of eight goals in the group stages, although his chances of bettering that mark may now be over.
A 4-0 triumph over Copenhagen and four points from two matches against Juventus means that Madrid only need a point to ensure qualification, but a shock defeat against Copenhagen on matchday four makes Galatasaray's situation far more precarious.
Recently-installed coach Roberto Mancini sees his side sitting second in the group on four points, level with the Danes and a point ahead of Juventus, whom they host on the final matchday.
Ahead of a game that will be played on his 49th birthday, Mancini told Uefa's official website: "Galatasaray are a very good team who have the potential to do well this season.
"It's never easy in the Champions League and our group is particularly tough. However, we can progress.
"I'm still confident of qualifying. We need to improve as a team but I am hopeful of a good result in our next game against Real Madrid.
"Then we will have everything to play for at home to Juventus on 10 December. As they say in football, never say never."