Spain and Real captain Casillas, 31, suffered the freak injury in a collision with team-mate Alvaro Arbeloa during the Copa del Rey quarter-final second leg against Valencia, and has been ruled out for up to three months with a fractured bone in his left hand.
Casillas was replaced by reserve keeper Antonio Adan and Jose Mourinho's side went on to secure a 1-1 draw that put them into the semi-finals 3-1 on aggregate to face Barcelona or Malaga, who meet later on Thursday.
"After carrying out initial x-rays it has been confirmed that Casillas has suffered a fracture at the base of the first metacarpal on his left hand," Real said in a statement on their website.
"It will be assessed again by a specialist later today to decide what treatment will be followed," they added.
"When I tried to close my fist it hurt. It's just the thumb. The fact that it has nothing to do with the wrist is good," Casillas, who had his left hand heavily bandaged, told the club's website.
The injury to a key figure comes at a delicate time for Mourinho with Europe's elite club competition resuming in just over two weeks.
Casillas has just been restored to the starting line up after Mourinho controversially dropped him for the league games either side of La Liga's winter break.
The decision provoked angry reactions from home fans and fuelled media speculation about possible dressing room rifts even though Real's defence has started to tighten up of late.
Former Spain U21 international Adan, who has spent his entire career playing second-fiddle to Casillas, was at fault for the goal conceded in Valencia on Wednesday, a low free kick he was slow to react to, but assistant coach Aitor Karanka defended him.
"Adan knows we have confidence in him," he said. "He played recently and was unlucky to get sent off. He knows he is young and has to progress, and that he has our backing."
The Copa del Rey and Champions League are Real’s priorities after falling well behind Barcelona in La Liga, but the loss of Casillas – one of the world’s top keepers – is a bitter blow to their chances.
"This season, where we aren't going to win the league, we have to think about the Champions League and Cup," Mourinho said in an interview with a French radio station on Wednesday.