The former Spain international feels the Blancos have what it takes to beat United if they put in a similar display as against Barca
The Santiago Bernabeu side were held to a 1-1 draw by United in the first leg, but Santillana remains optimistic about their chances of making it to the next round.
"United don't like having the ball too much, they will probably allow Madrid to dominate possession and play a similar game to the one they played at the Bernabeu," Santillana told Efe.
"The approach used against Barca will suit us perfectly against United. If Madrid can exert the same pressure as they did against Barca, Man United will find it very difficult to build moves from the back.
"And for the speed with which Madrid have on the break, a plan like that would function well, I think. We will be up against more difficulties, though, because they won't let us hit them on the break like Barca do."
The return at Old Trafford is scheduled to take place on March 5.