Cristiano Ronaldo begins his three-match suspension as Carlo Ancelotti's men look to bounce back from last weekend's dropped points.
Carlo Ancelotti's side is in a three-horse race for the league title, placed third behind holder Barcelona and current leader Atletico Madrid after only drawing with Athletic Bilbao on Sunday.
The dropped points were made worse when Ronaldo was sent off following an incident with Carlos Gurpegui 15 minutes from time. Ronaldo's dismissal earned him a three-match ban, which will see him miss the visit of a side that have proven stubborn opposition for the Blancos in recent encounters.
Villarreal has denied Madrid wins in its last two meetings, drawing 1-1 in March 2012 thanks to an 83rd-minute Marcos Senna goal before Giovani dos Santos earned his side a 2-2 draw earlier this season with a goal 20 minutes from time.
Both those results came at the Camp El Madrigal and Madrid will be more confident ahead of Saturday's fixture given its recent record against Villarreal at the Santiago Bernabeu.
Madrid has scored 13 times on Villarreal's last three visits, conceding four times, and Ancelotti will be eager to pile the pressure on Atletico and Barca, which play later on Saturday and Sunday respectively.
Marcelino Garcia Toral's men have won three of their last five away games in La Liga and sit just three points off Athletic Bilbao, which occupies the final Champions League spot.
However, their recent resurgence on the road will be put to the test against Madrid, with the hosts — who have not conceded at the Bernabeu in La Liga since Nov. 9 — having lost only once at home in the top flight this season.