Zinedine Zidane's side, who will face Borussia Dortmund, Tottenham and APOEL in the Champions League following Thursday's draw, have already won the UEFA Super Cup and the Spanish Super Cup this season and are also favourites to retain La Liga for the first time since 2007-08.
Here, Goal takes a look at everything you need to know ahead of Madrid's match versus Valencia...
REAL MADRID INJURIES
Central defender Jesus Vallejo is still sidelined, but Raphael Varane should be available despite missing training on Thursday to receive treatment on a niggling injury that saw him sit out the game against Fiorentina on Wednesday.
Mateo Kovacic also missed training on Thursday, but both the Croatian midfielder and Varane took part in Friday's session.
REAL MADRID SUSPENSIONS
Cristiano Ronaldo received a five-match ban for his red card and push on the referee in the first leg of the Spanish Supercopa at Camp Nou two weeks ago and still has to serve three more games of that suspension.
Meanwhile, Sergio Ramos is also banned after his red card at Deportivo last weekend, with Madrid losing their appeal to have the captain reinstated for the game against Valencia.
REAL MADRID POTENTIAL STARTING LINE-UP
Real Madrid are down to the bare bones in central defence, with Sergio Ramos suspended and Jesus Vallejo injured, but Raphael Varane seems to have shaken off a minor problem to start on Sunday with Nacho at the back.
Elsewhere, Gareth Bale is likely to feature in attack alongside Karim Benzema, with Isco just behind in a playmaker role as Cristiano Ronaldo continues to serve his five-match ban for the red card and subsequent push on the referee in the Clasico at Camp Nou earlier this month.
Casemiro, Luka Modric and Toni Kroos are all available and are likely to line up together in what is Zinedine Zidane's first-choice midfield trio.
VALENCIA TEAM NEWS
Valencia have had their troubles in recent times, but the Mestalla-based club kicked off La Liga with a 1-0 win at home to Las Palmas last weekend.
That was right-back Joao Cancelo's last game for the club as he moved to Inter earlier this week on loan with a view to a permanent transfer at the end of the season.
Coach Marcelino Garcia Toral will hope to return Valencia to the upper echelons of Spanish football after a decline for the club in recent seasons and a 12th-placed finish in the Primera Division last term.
Former Madrid centre-back Ezequiel Garay is set to miss this match through injury, while Jeison Murillo and Geoffrey Kondogbia are expected to make their Valencia debuts.
BEST OPTA MATCH FACTS
Real Madrid have just lost two of their last 16 league games against Valencia (won nine, drawn five), both of them at Mestalla and by the same result (2-1 in February 2017 and again in January 2015).
Valencia haven’t won in any of their last nine La Liga games at the Santiago Bernabeu (drawn four, lost five), but they have drawn four of the last six.
Real Madrid could become the first team in the top five European leagues to score in 70 consecutive games in all competitions (having currently netted in their last 69 competitive fixtures).
On the first match day, Gareth Bale ended his worst ever run without scoring for Real Madrid in all competitions (10 games).
UK TV COVERAGE & KICK-OFF TIME
Real Madrid versus Valencia kicks off at 22:15 CEST at the Santiago Bernabeu and will be shown live from 21:10 UK time on Sky Sports football.