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.
Guardiola will step down at the end of the campaign when his assistant Tito Vilanvoa is to replace him.
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.
Valencia, in pole position to secure the third automatic Champions League qualification slot, are 29 points adrift in third on 58 from 36 games.
They are three points ahead of Malaga in fourth, who, if they can hang on to their place, will have the chance to reach the Champions League for the first time via the final qualifying round in August.
FAVOURITES FOR THIRD
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.
At the foot of the table, basement side Racing Santander are relegated but 19th-placed Sporting Gijon and 18th-placed Real Zaragoza still have chances to survive.
Sporting host Real Betis and Zaragoza are at home to Racing, while Rayo Vallecano, Villarreal and Granada in 15th could all still get dragged down to the second division.
