La Real, winners of the 2019-20 edition, are looking to reach the semi-finals for the second time in three years.
They managed to oust Diego Simeone's Atletico Madrid from the competition in the last round, courtesy of goals from Adnan Januzaj and Alexander Sorloth.
Betis, meanwhile, overcame city rivals Sevilla in a tense derby, fighting back from a goal down to win 2-1 at home with Sergio Canales netting the winner in the 73rd minute.
They're aiming to reach the last-four of the competition for the first time since 2019.
Real Sociedad vs Real Betis Head-To-Head
In the previous 38 clashes between the sides, the spoils are closely shared.
La Real have won 14 times against Real Betis, who've emerged victorious on 13 occasions.
Los Verdiblancos are unbeaten in their last three clashes against the Basque Country outfit, winning each of their last two encounters.
Real Sociedad Form Guide (all competitions): D-W-W-W-D
Real Betis Form Guide (all competitions): W-D-W-W-W
Real Sociedad vs Real Betis Team News
La Real have quite a few injury concerns, as Ander Barrenetxea (thigh muscle rupture), Nacho Monreal (knee Injury) and Carlos Fernández (cruciate ligament rupture) are all set to miss the clash.
Head coach Imanol Alguacil is unlikely to make changes to the side that beat Atletico Madrid in the last round.
Injured: Ander Barrenetxea, Nacho Monreal, Carlos Fernández
In comparison, Manuel Pellegrini will be missing Martin Montoya, as the defender recovers from an Achilles tendon problem.
Injured: Martin Montoya
Real Sociedad vs Real Betis Predicted XI
Real Sociedad (4-4-2): Álex Remiro; Joseba Zaldúa, Aritz Elustondo, Robin Le Normand, Aihen Muñoz; Adnan Januzaj, Ander Guevara, Mikel Merino, Mikel Oyarzabal; David Silva, Alexander Sørloth.
Real Betis (4-2-3-1): Joel Robles; Héctor Bellerín, Germán Pezzella, Edgar González, Álex Moreno; Guido Rodríguez, William Carvalho; Sergio Canales, Nabil Fekir, Juanmi; Borja Iglesias.
Real Sociedad vs Real Betis Prediction
Both teams are coming off the back of huge results in their last round and each possesses a highly talented squad at their disposal.
Expect an intense affair but Sociedad, who haven't beaten Betis in three games, should come through on penalties if there's no separating them in normal time.
Prediction: Real Sociedad 2-2 (3-2) Real Betis