Barcelona can confirm their second consecutive La Liga title in Madrid if they win at Atletico on Sunday.
The Catalan club are unbeaten in the league since their 2-1 defeat at Real Madrid in March and have built an eight-point lead over their rivals.
With Real having just three games remaining, compared to Barca's four, a victory at the Vincente Calderon will give them an unassailable lead, irrelevant of the result of Real's trip to Espanyol.
Lionel Messi, who has been struggling with a hamstring injury since the beginning of April and looked on from as a substitute as his side crashed out of the UEFA Champions League to Bayern Munich, came off the bench on Sunday to help secure all three points against Real Betis.
Trailing 2-1 at half time, David Villa scored an equaliser before being replaced by Messi for the last 34 minutes.
The Argentine forward went on to score twice, his 45th and 46th league goals of the season and the 21st straight La Liga match in which he has scored, to seal a 4-2 win for Tito Vilanova's side.
The title will be Vilanova's first at the helm after he took over from Pep Guardiola last summer.
Atletico secured third place and a spot in next season's Champions League with a 3-1 victory at Celta Vigo on Wednesday and still harbour slim hopes of overhauling Real Madrid in second, sitting eight points adrift with three to play.
Real Madrid make the opposite trip to Barcelona as they visit Espanyol on Sunday.
Real look certain to finish second in La Liga after hammering nine-man Malaga 6-2 on Wednesday, their sixth-straight league win.
That match saw Cristiano Ronaldo score his 200th goal for the club, as well as miss a penalty, and Jose Mourinho will be keen for his side to continue their impressive form ahead of the Copa del Rey final against city rivals Atletico next Friday.
Elsewhere, the battle for the fourth and final Champions League position will take another turn when Valencia, two points and one place behind fourth-placed Real Sociedad, travel to Rayo Vallecano on Sunday before Sociedad host Granada on Monday night.
And Malaga will be keen to bounce back from their heavy defeat in the capital on Wednesday and tighten their grip on sixth place when they face Sevilla at home Sunday, although Manuel Pellegrini's side will not be able to take their place in the UEFA Europa League next season following a ban for irregular finances.
At the foot of the table, just four points separate the bottom five clubs.
Bottom side Mallorca, on 29 points and four adrift of safety, travel to Athletic Bilbao on Saturday while the two other teams occupying the relegation zone are also on the road; Deportivo La Coruna visit mid-table Real Valladolid and Celta Vigo go to Real Betis, who are in prime position to profit from Malaga's inability to play in Europe next year.
Real Zaragoza and Osasuna both sit one point above the drop zone. Zaragoza can pile on the pressure to those teams below them when they get the weekend's matches started on Friday night at Levante and Osasuna welcome eighth-placed Getafe on Saturday.