Zinedine Zidane's side lost 2-1 to Leganes at the Santiago Bernabeu to crash out on away goals and that leaves the Champions League as their only realistic hope of silverware this season.
Here, Goal takes a look at everything you need to know ahead of their tough trip to third-placed Valencia on Saturday...
REAL MADRID INJURIES
Captain Sergio Ramos returned to action in midweek after a muscle injury suffered in training earlier this month, but has been ruled out for another two weeks after aggravating his condition.
Isco has also been confirmed as an absentee, but Karim Benzema should also be fit enough to start after making back-to-back substitute appearances.
Midfielder Dani Ceballos is doubtful, though, while defender Jesus Vallejo misses out.
REAL MADRID SUSPENSIONS
Zidane has no players suspended for the game against Valencia.
REAL MADRID POTENTIAL STARTING LINE-UP
For the first time this season, Zidane is set to field his strongest XI all together and that means a first start for Gareth Bale, Benzema and Cristiano Ronaldo in attack since last season's 3-2 loss at home to Barcelona in April.
Both Bale and Ronaldo started last weekend's 7-1 win over Deportivo La Coruna at the Santiago Bernabeu, when Benzema came on as a subsitute.
The French forward also featured - and scored - in the 2-1 loss to Leganes on Wednesday and is now ready to feature from the outset at Mestalla.
In defence, Sergio Ramos should start again after making his return from injury in midweek.
VALENCIA TEAM NEWS
Gabriel and Ruben Vezo are both suspended after they were sent off against Las Palmas last weekend, the Brazilian defender also sidelined after picking up a knee injury in the Copa del Rey in midweek.
Midfielder Dani Parejo and left-back Jose Luis Gaya both return from bans and will go straight back into the side, but Ezequiel Garay is the side's only fit central defender and midfielder Francis Coquelin could be asked to fill in at the back.
Attacking midfielder Carlos Soler is doubtful for Valencia, winners on penalties in the Copa del Rey against Alaves on Wednesday and third in La Liga, five points ahead of Madrid.
TV COVERAGE & KICK-OFF TIME
Valencia versus Real Madrid kicks off at 16:15 local time at Mestalla on Saturday. Due to old broadcasting laws in the UK, it cannot be shown live at that time, but delayed coverage is available on Sky Sports Main Event and also Sky Sports Football from 17:30 GMT.
In the United States (US), the match is live on BeIN Sports and kicks off at 10:15 ET.
BEST OPTA MATCH FACTS
Valencia have only won two of their last 17 games against Real Madrid in La Liga (drawing six and losing nine), the last one at Mestalla in February 2017.
Valencia have scored exactly two goals in eight of their last nine games against Real Madrid in La Liga.
Marcelino's men have only lost one of their 10 home league games this season (winning seven and drawing two). Their sole defeat was a 1-0 loss against Villarreal in December.
Cristiano Ronaldo has been directly involved in 13 goals in his last nine meetings in La Liga against Valencia (10 goals and three assists).
Marcelino has only won two of his 13 games as a manager in La Liga against Real Madrid, one in charge of Recreativo and the other with Villarreal (losing eight and drawing three in the other fixtures).