Benzema has been nursing a calf problem this week which he picked up after scoring two goals in a 3-0 win at Real Mallorca on Monday.
The 34-year-old was unable to train on the eve of the game against Xavi Hernandez's side at the Santiago Bernabeu.
Benzema is La Liga's top scorer this season with 22 goals from 25 games. He has also provided the most assists with eleven so far.
Benzema will not be able to link up with the French national team ahead of next week's international break as well.
Real Madrid manager Carlo Ancelotti believes the striker's absence could be a blessing in disguise ahead of the business stage of the season, which includes a date with Chelsea in the Champions League quarterfinals.
"Both [Benzema] and Mendy can't play and won't go to France either. They stay in Madrid," Ancelotti said at Saturday's pre-match press conference.
"He hasn't trained with the group. He still has some discomfort.
"Karim is a very important part, because he finishes all the work, but without him, you have to keep that work and look for different solutions.
"It is already decided who is going to play [in his place]. But I'm not going to tell you."
"He is a player who is 34 years old and sometimes it can happen to him.
"They are very minor annoyances and he has recovered very quickly. When he has come back, he has made a difference.
"We have another two weeks to work with him and then he will make a difference again.
"It doesn't worry me that he won't play tomorrow because we have time for him to play at the end of the season and make a difference."
Real Madrid are ten points clear at the top of the La Liga table.
