Luka Modric and Marcelo have sustained respective abductor and hamstring injuries, Real Madrid confirmed on Monday.
The pair were substituted during Saturday's 2-1 La Liga success at home to Malaga, as the European champions bounced back from successive defeats to Sevilla and Celta Vigo.
But the win came at a cost, with head coach Zinedine Zidane expressing his frustration at seeing the pair added to an injury list that already includes Gareth Bale, James Rodriguez, Dani Carvajal, Pepe, Danilo and Fabio Coentrao.
He said: "I am a bit upset with the injuries. My mind is a bit blown. We have a big game Wednesday and injuries are screwing it up.
"A lot of the season is still left and like I always say, we will be needing every player."
A club statement confirmed Modric had suffered an injury to his right abductor, while Marcelo has a grade II tear in his left hamstring.
Madrid gave no indication of a possible recovery for timescale for either player, although they seem certain to miss the Copa del Rey quarter-final second leg at Celta on Wednesday, when Zidane's side will look to overturn a 2-1 deficit.