Jose Mourinho's champions Real, with 94 points and two games left to play, head to Granada on Saturday with their sights now set on beating the league points record of 99 set by Pep Guardiola's Barcelona in 2010.
Barca, seven points back in second, play their final home game against city rivals Espanyol, when the Nou Camp will seek to give Guardiola a fitting send off after four trophy-ladened seasons at the helm.
The two Spanish giants, the world's richest clubs by revenue, have once again left the rest of the league trailing in the distance this season.
Unai Emery's Valencia can assure their return to the group stages of the competition and a third consecutive 'champion of the rest of the league' tag with a victory at home to regional rivals Villarreal.
"We are assured of a top four finish, but the satisfaction will come from being third," Emery, who is expected to leave at the end of the campaign, said after their 4-0 victory over Osasuna on Wednesday.
"We are favourites to secure this place, but Malaga are strong and can still reach us."
Qatar-owned Malaga, one of the league's biggest spenders in the closed season, have a difficult trip to play direct rivals for Europe, Atletico Madrid.
The Europa League finalists are sixth with 50 points, two behind Levante in fifth, and the two are on course to qualify for Europe's second-tier club competition next season.
"The lads are making a great effort and we are going to fight while there are still possibilities," Atletico coach Diego Simeone said when questioned about the tiredness of his players after their 1-1 draw at home to Real Sociedad.
