Gerardo Martino's Barcelona have endured a near flawless start, amassing 34 points from a possible 36 with a 0-0 draw against Osasuna the only blemish on their record.
A goal from Alexis Sanchez secured victory over city rivals Espanyol last time out, the club’s third successive league win.
Barcelona will be confident of making it four in a row given this weekend’s opponents sit 18th with just nine points to their name.
Betis have lost four of their last five La Liga fixtures and were beaten 3-2 at Malaga in their previous game as Samu grabbed a 94th-minute winner.
Second-placed Atletico are just one point behind Barcelona after winning 11 out of 12 league matches this term.
Diego Simeone's men have bounced back strongly since losing to Espanyol in October, racking up victories over Betis, Granada and Athletic Bilbao.
Yet they face a difficult challenge when they hit the road to face off against Villarreal.
Marcelino Toral's charges have impressed since gaining promotion from the Segunda Division and lie fourth with 23 points.
Elsewhere on Sunday, beleaguered Valencia manager Miroslav Djukic will hope to see his side earn a second straight league win when they welcome Real Valladolid, while Espanyol host Sevilla.
On Saturday, third-placed Real Madrid will aim to close the six-point gap to Barcelona as they host Real Sociedad at the Bernabeu.
Carlo Ancelotti's side have bounced back from losing El Clasico with consecutive triumphs, a 7-3 rout of Sevilla followed by a nervy 3-2 success at Rayo Vallecano.
One problem for Ancelotti could be who to utilise in goal, after Iker Casillas' fine performance in the 2-2 UEFA Champions League draw with Juventus in midweek.
Other fixtures on Saturday see Getafe welcome Elche, Levante travel to Athletic Bilbao and Celta Vigo host Rayo Vallecano.
On Friday, Almeria have the opportunity to leapfrog Osasuna when the two do battle at Estadio El Sadar, while Malaga travel to Granada.
