Spanish number one and Madrid captain Casillas has been ruled out of the Champions League tie with a broken hand.
Despite acknowledging the fact that Real have other keepers, De Gea has insisted that Casillas will be a "great loss" for Los Blancos.
"Every time Iker Casillas is not there, he is a great loss," he told reporters.
"It is a great loss because he is the captain of Real Madrid and Spain. But Real have two other keepers who can play as well as Casillas does."
De Gea joined United in the summer of 2011 from Real's city rivals Atletico Madrid.