Real Madrid will have to back up from mid-week European action when they travel to Elche on Sunday, while Barcelona host Malaga on Saturday in La Liga.
Barca can go provisionally top with a win at Camp Nou, and Real will be battling fatigue after playing in Germany on Wednesday - when they were 2-0 winners over Schalke in their last 16 first leg.
While trying to defend their European crown, Real are also trying to reclaim the domestic title - something midfielder Toni Kroos said was a priority.
"Every game in the Champions League is of the highest international level, against the best players in Europe. Battles like that help you gain experience and evolve," Kroos told UEFA.
"We all want [to win the Champions League], but first we must try to remain top of La Liga. Winning the league title must be a priority for us."
Real have won all three clashes against Elche, although their one trip to the Estadio Manuel Martinez Valero in 2013 saw them need a late Cristiano Ronaldo penalty to win.
Ronaldo (28 goals) leads the golden boot race in Spain from long-time nemesis Lionel Messi (26).
Messi has scored in nine of his past 12 games in the Spanish top flight - including four hat-tricks and two braces.
The Argentine superstar has not scored against Malaga in his past two league matches against the current seventh-placed outfit, with Barca failing to break through against them earlier this season in a 0-0 stalemate.
Later on Saturday, fourth-place Valencia are away at bottom side Cordoba, champions Atletico Madrid will look to bounce back from a last-start defeat when they host Almeria, while Deportivo La Coruna welcome Celta de Vigo.
On Sunday, Sevilla can continue their push for top-four honours when they travel to Real Sociedad, Athletic Bilbao will look to avenge their last-gasp loss to Rayo Vallecano from earlier this season, while Villarreal and Eibar - two sides who have hit poor form of late - go head to head.
Monday's lone fixture sees Granada on the road at Levante - both sides occupy relegation zone spots - while the weekend's action begins when Getafe host Espanyol.