Los Blancos suffered a first defeat of the season last time out, going down 1-0 to newly-promoted Cadiz, and will be looking to quickly hit back.
However, Zinedine Zidane's men have a daunting trip to Barcelona to come next weekend and may well have to rotate their squad for this match.
Here, Sports Mole looks at how Madrid could line up against Ukrainian champions Shakhtar.
Skipper Sergio Ramos was taken off at half time against Cadiz with a minor knee injury and will surely not be risked in midweek.
Karim Benzema played the full 90 minutes once again last time out and could possibly do with a rest ahead of the first El Clasico of the season.
Should that be the case, Luka Jovic may have another chance to prove that he can make it as a Madrid player, with the likes of Martin Odegaard, Alvaro Odriozola and Eden Hazard all nursing injuries.