The timing could barely be worse. With the Clasico at Barcelona just around the corner, Gareth Bale is injured and the 27-year-old will be sidelined for up to three months after ankle surgery on Tuesday. It's terrible news for Real Madrid.
Bale missed Madrid's UEFA Super Cup clash against Sevilla in Trondheim back in August after returning late from his holidays because of his run to the semi-finals of Euro 2016 with Wales. But he has been virtually ever-present since then, featuring in 11 of his side's 12 games in La Liga and in all five in the Champions League - each of them as a starter.
With Cristiano Ronaldo still sidelined following the knee injury he picked up in the final of Euro 2016, Bale began the season with a bang at Anoeta, scoring two of his team's goals in the 3-0 win away to Real Sociedad. Since then, he has also netted versus Eibar, home and away to Legia Warsaw and a double in the 3-0 win over Leganes.
Against Atletico on Saturday night, he was used in a deeper role in midfield and set up Ronaldo's third in a memorable Madrid derby win for his team. That came after Zidane had picked a different formation to compete with Diego Simeone's side. With Bale until 2017 after limping off with an ankle injury in Lisbon on Tuesday, Zidane must shuffle the pack again ahead of the Clasico.
Real Madrid are at home to Sporting Gijon on Saturday, with a Copa del Rey clash against Cultural Leonesa to come on Wednesday night - also at the Santiago Bernabeu. And while the Blancos should be able to negotiate both of those fixtures comfortably, the trip to Barcelona represents another type of test altogether.
Real remain unbeaten in all competitions this term, while Zidane's side have not lost at all in any of their last 30 matches - a streak stretching all the way back to the 2-0 loss away to Wolfsburg in April.
That remarkable run will be hard to maintain without Bale. The Welshman has been perhaps Madrid's most important player in 2016-17 so far and is playing his best football since moving to Real in the summer of 2013. With the Camp Nou clash coming up on December 3, he is the man they would have wanted most to be fit.
But he is not and Zidane will need to devise a new plan, just as he has on several occasions already this season. Without Ronaldo, Bale and Karim Benzema in the UEFA Super Cup, it was Marco Asensio, Sergio Ramos and Dani Carvajal who stepped up. And with a string of injuries to key players such as Luka Modric, Casemiro, Toni Kroos, Ramos, Alvaro Morata, Keylor Navas and more this campaign, others have come in and played their part.
James Rodriguez was excellent in September when Modric was out, while Mateo Kovacic has emerged as a fine option in the absence of Casemiro, Nacho and Raphael Varane were superb in central defence against Atletico, with Isco incredibly impressive in the playmaker role that same night.
In fact, Madrid's squad is so strong these days that they can cope without almost anybody and while Zidane has long maintained that the idea is to play with Bale, Benzema and Ronaldo in attack, he has found solutions when those players have been unavailable.
The Frenchman can choose several different options in Bale's absence, be it 4-3-3 with Lucas Vazquez in the Welshman's role on the right, 4-4-2 with more midfielders in the team or even 4-2-3-1.
So while losing Bale to injury just before the Clasico is evidently a big blow, it is not necessarily a fatal one for Real Madrid.