The Yellow Submarine drew 2-2 with los Blancos at El Madrigal earlier this season and will look to equal or better that result on Saturday.
Dos Santos has never experienced a win at the capital-based club, however he has faith that Marcelino's men can come away from La Liga's title challenger with all three points this weekend.
"I've never won there," the 24-year-old told AS. "The only positive thing I have against them is the draw earlier this season with Villarreal. To beat Madrid at home is very difficult.
"Villarreal have never won there either. But that's history and in the past, we hope to change history and to win for the first time there."
Madrid star Cristiano Ronaldo will miss the game as he serves the first game of a three-match La Liga ban following last weekend's red card, but Dos Santos thinks the Blancos have enough quality in their squad to thrive without him.
'It's a very important factor and it can not be ignored," the Mexico international added. "But it's equally important that they have a lot of quality players who can replace him."
Villarreal, which was promoted back into the top tier for this season, sits fifth in La Liga behind Atletico Madrid, Barcelona, Real Madrid and Athletic Bilbao.