The 31-year-old shot-stopper and club captain has failed to recover in time from injury despite travelling with the rest of the squad for the game at Old Trafford
The 31-year-old goalkeeper has been struggling with injury since fracturing his hand during the team's 5-0 over Valencia back in January and he was originally included in the travelling party for the clash.
However, Mourinho has revealed that the side will be without their captain for the second leg, with Diego Lopez set to keep his place between the sticks.
"Everyone is fit and ready to play, with the exception of Iker Casillas," Mourinho told reporters.
With the first leg producing a 1-1 draw, Mourinho has admitted that his side are up against it to turn the tie around at Old Trafford, and despite their recent good form back home in Spain which has included two wins over Barcelona, that it could be a tight affair.
He added: "I think Manchester United will be very defensive when we have the ball and it'll be the same for us when they have the ball.
"We are effectively behind in the scoreline on away goals. It's only 1-1, we will have to attack and be bold.
"We come here after two wins, if we come here after two defeats, our feeling would be the same.
"I won, I lost, I draw, last time I came here I lost with Inter in the CL. I have everything against manchester United. I don't care about records. What I care is that tomorrow this kind of match anything can happen."