That 2-2 tie at Balaidos left Los Blancos provisionally 14 points behind leaders Barcelona and their hopes of retaining the title they won last season now look slim, despite a game in hand.
Here, Goal takes a look at everything you need to know ahead of their trip to the Santiago Bernabeu on Saturday...
REAL MADRID INJURIES
Captain Sergio Ramos suffered a muscle strain in training recently and is still not ready to return for Real.
Striker Karim Benzema also misses out due to an injury sustained in the Clasico defeat to Barcelona last month and midfielder Marcos Llorente is doubtful with a shoulder problem he picked up in the 2-2 draw against Numancia in the Copa del Rey on Wednesday.
REAL MADRID SUSPENSIONS
Right-back Dani Carvajal was suspended for the trip to Balaidos following his red card in the Clasico loss to Barcelona before Christmas, but the Spain defender is available again for Los Blancos and Zidane has no other players banned for Saturday's game against Villarreal.
REAL MADRID POTENTIAL STARTING LINE-UP
With Ramos still out, Nacho and Raphael Varane should start in central defence for Real Madrid at home to Villarreal.
Meanwhile, Carvajal is set to return at right-back after missing the 2-2 draw at Celta Vigo through suspension.
In attack, Gareth Bale will start alongside Cristiano Ronaldo in the absence of Benzema. The Welsh winger scored both of Madrid's goals at Balaidos and was rested for the cup clash at home to Numancia on Wednesday.
VILLARREAL TEAM NEWS
After back-to-back wins away to Celta Vigo and Valencia, Villarreal could only draw 1-1 at home to Deportivo in La Liga last weekend.
The Yellow Submarine beat Leganes 2-1 at the Estadio de la Ceramica on Wednesday, but went out of the competition on away goals.
In La Liga, Javi Calleja's side are in sixth, just four points behind Madrid, but they will be without midfielder Bruno Soriano, defender Ruben Semedo and reserve goalkeeper Andres Fernandez on Saturday, while forwards Nicola Sansone and Roberto Soldado are doubtful.
TV COVERAGE & KICK-OFF TIME
Real Madrid versus Villarreal kicks off at 16:15 local time at the Santiago Bernabeu on Saturday and, due to boadcasting laws in the UK, it cannot be shown live at that time. However, it will be televised later on Sky Sports Mix and Sky Sports Football (via the red button) from 17:30 GMT.
In the United States (US), Real against Villarreal is live on BeIN Sports and kicks off at 10:15 ET.
BEST OPTA MATCH FACTS
Real Madrid have won five of their last six La Liga home games, but lost the last one 3-0 to Barcelona. The last time Los Blancos lost consecutive games at home in the competition was in May 2009 under Juande Ramos.
Villarreal have won their last two away league games, both by the same scoreline (1-0). The last time they won three in a row away from home was in March 2017.
Cristiano Ronaldo has scored 12 goals in his 13 league games against Villarreal in La Liga, more than any other player in the competition.
Carlos Bacca has been involved in six of Villarreal’s last 10 goals in La Liga (three goals, three assists).
Gareth Bale is the only La Liga player to have scored four or more goals this season after playing fewer than 500 minutes (498).