Several players will return from suspension for Los Blancos, who beat Real Sociedad at the Anoeta in their last outing and have climbed to fourth place in the standings.
Betis have two wins from four matches and are often tricky customers, but their defensive issues this season―seven goals conceded already―and the return of Cristiano Ronaldo make Real heavy favourites.
Here's everything you need to know about the upcoming fixture.
Date: Wednesday, September 20
Time: 9 p.m. BST/4 p.m. ET
Venue: Estadio Santiago Bernabeu, Madrid
TV Info: Sky Sports Red Button (UK), BeIN Sports (U.S.)
Per WhoScored.com, Marcelo and Ronaldo will return from suspension for Real and both are expected to start. Toni Kroos could also return from injury, while Karim Benzema and Mateo Kovacic remain sidelined.
Alin Tosca and Joel Campbell are unavailable for the visitors, who could also be without Juanjo Narvaez.
After back-to-back draws that had some doubting Real's early-season form, Los Blancos made a huge statement in the Basque Country on Sunday. The 3-1 win over an in-form Real Sociedad was impressive and saw some key contributions from vital players.
Gareth Bale hasn't been at his best this season and his goal should give him a huge confidence boost. The Wales international displayed his awesome athleticism to force the strike, drawing praise from fans and pundits alike as a result. Even former Los Blancos man Alvaro Arbeloa was in awe:
Álvaro Arbeloa @aarbeloa17
I love you, @GarethBale11. ⚡️2017-9-17 20:08:20
On Wednesday, Ronaldo will play his first La Liga match of the season, as his suspension had sidelined him from domestic action so far.
The 32-year-old is likely to feast on Betis―in his lone outing since the Spanish Super Cup, he scored twice against Apoel Nicosia FC in the UEFA Champions League, showing how dangerous he can be when he's well-rested.
The biggest question is where the Portuguese star will play. Borja Mayoral got on the scoresheet against Sociedad, but he could be sacrificed in favour of Ronaldo, with Bale and Marco Asensio playing on either side of the veteran.
Alternatively, Asensio could be rested with Mayoral playing centrally and Ronaldo out wide. With tricky outings at Alaves and Borussia Dortmund on the horizon, it might not be a bad idea to rotate the squad against a Betis team that has yet to keep a clean sheet this season.