An injury-time Sergio Ramos equaliser ensured Madrid maintained a six-point cushion over Luis Enrique's side when the sides met earlier this season, and with Los Blancos currently three points ahead with a game in hand, victory would leave Barca trailing by the same margin with only five to play.
Real are unbeaten since February, winning 10 of their last 12 games. In contrast, Barcelona have won just two of their previous five in all competitions and were dumped out of Europe in midweek.
The Catalans' task is made all the more difficult given forward Neymar's suspension. But Barca coach Luis Enrique insisted after their 3-0 aggregate defeat by Juventus that his side would be ready to bounce straight back up.
"It will be difficult to lift my players up after this, but it will be easy to motivate them. We have the best stimulus that any Barcelona fan could ask for which is that we play against our eternal rival. There's no better place to go than the Bernabeu.
"We have the chance to get back in the fight for La Liga in a six-pointer against the side top of the league. I love being involved at a club as ambitious as this."
Madrid will be looking to a rejuvenated Cristiano Ronaldo, who has scored five in his last two appearances and netted his 100th Champion League goal with a hat-trick against Bayern Munich on Wednesday.
The Portuguese scored the goal that essentially sealed Madrid's last La Liga crown in 2012's 2-1 victory over the Catalans and will be looking to repeat the feat for Zinedine Zidane's men this weekend.
"I don't know if there's a category for him. What you see Cristiano doing is really impressive. The goals, the way he finishes them, in such key, important moments," said Zidane of the No. 7.
"He always knows when there's an important occasion, he's going to be there. It is out of any sort of category. There are few players who can to do what Ronaldo has done and we all know that."
Madrid will be without defenders Pepe and Raphael Varane for the game, while Dani Carvajal, Toni Kroos and Gareth Bale all have question marks over their fitness heading into the game.
Elsewhere, Atletico Madrid will look to further tighten their grip on third place as they travel to Espanyol on Saturday, while the weekend's action culminates on Monday with a Basque derby as Eibar host Athletic Bilbao.
(Reporting by Joseph Cassinelli, Editing by Angus MacSwan)
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