The French striker was taken off during the match against Celta Vigo on Wednesday after he sprained his ankle and his trainer does not expect him to recover in time for the next game.
"I think Benzema will not play tomorrow. For me, if he has picked up an injury of any kind he should not be fit to play two days later," Mourinho told a press conference.
The Blancos' boss went on to praise Espanyol coach Javier Aguirre for the style of football he plays and the work ethic that he brings to his teams.
"Espanyol have a coach that I really get on with. His teams always play attractive football and have a top work rate," Mourinho said.
"I think that Aguirre will build on the foundations that the last coach put in place and start getting some good results very soon."