Hosting Madrid have been the favourites with the bookmakers to claim the victory, having never lost previously to United on home soil. It is a viewpoint that is shared by the former Dutch international.
"I think the pressure is on Madrid. They have the pressure of losing the league already and they have in the back of their minds that they have to go to Old Trafford," Van Nistelrooy told Sky Sports News.
"I think Madrid will come out on top today. I think United will give possession and use their fast forwards to try and get an away goal."
Van Nistelrooy spent five years with United up until 2006, before joining Madrid for another four seasons.