Los Blancos will head into the fixture in second place in the league table, while the Champions League-chasing hosts are sitting in fourth position.
Match preview
After achieving a fifth-place finish last season, Athletic are now looking to secure Champions League qualification for the first time since 2013-14 after showcasing their top-four credentials in their 15 league games this season.
Athletic have won seven, drawn five and lost three of their 15 La Liga matches, leaving them in fourth position and above fifth-placed Villarreal on goal difference.
Los Leones showed great character in their most recent outing against Rayo Vallecano, coming from behind to claim a narrow 2-1 victory thanks to Oihan Sancet's second-half brace.
Sancet's match-winning display secured Athletic a third consecutive victory and extended their unbeaten run to nine matches in all competitions, ensuring Los Leones have not lost a competitive game since they fell to a 2-1 defeat against Girona on October 6.
After enjoying a successful trip to Vallecas, Ernesto Valverde's side will now return to the home comforts of San Mames, where they have won six of their previous eight competitive matches (D2).
However, they have not beaten Los Blancos in a league game at San Mames since Aritz Aduriz scored the decisive goal in a 1-0 victory in March 2015 when Valverde was in his second stint as Athletic boss and Carlo Ancelotti was in his first spell as Real Madrid manager.
Real Madrid would have been bitterly disappointed after they fell to a 2-0 defeat in last week's Champions League away clash against Liverpool - a result that represented a third loss in four European games and has left Los Blancos down in 24th place in the league place.
But while they may be struggling in the Champions League, Real Madrid are starting to build momentum on the domestic front, winning three consecutive league games without conceding to take advantage of Barcelona's three-game winless run in La Liga (D1, L2).
Jude Bellingham took over penalty duties for Sunday's home clash against Getafe, keeping his composure to net a 30th-minute spot-kick before Kylian Mbappe found the net to double his side's advantage in a dominant first half at the Santiago Bernabeu.
Los Blancos were unable to add to their tally in the second period, but crucially, they stood firm at the opposite end of the pitch to claim their seventh league clean sheet of the season, ensuring they finished the weekend just one point behind leaders Barcelona with a game in hand.
Real Madrid will continue their title defence in their upcoming clash against Athletic, with the visitors looking to make it 22 consecutive La Liga away games without defeat since they lost to Atletico Madrid in September 2023.
The European champions will be fully aware of the tough test that awaits them on Wednesday, but they will fancy their chances of claiming all three points after winning each of their last five away games against Athletic, including a 2-0 victory in last season's visit to San Mames.
Athletic Bilbao La Liga form:
W
D
D
D
W
W
Athletic Bilbao form (all competitions):
D
W
D
W
W
W
Real Madrid La Liga form:
W
W
L
W
W
W
Real Madrid form (all competitions):
L
L
W
W
L
W
Team News
Athletic have confirmed that experienced midfielder Ander Herrera has picked up a hamstring injury, ruling him out of Wednesday's home fixture.
Sancet is expected to shake off a slight ankle issue to take his place in the starting lineup after he came off the bench to score a brace in Sunday's 2-1 win over Rayo.
Benat Prados is set to return to the starting lineup after serving a one-match suspension, while there could also be recalls for Oscar de Marcos and Dani Vivian.
Valverde will have to decide whether to keep faith with Julen Agirrezabala or bring in Unai Simon after the Euro 2024 winner recently returned to the fold following a lengthy spell on the sidelines.
As for Real Madrid, they remain without midfielder Eduardo Camavinga and forward Vinicius Junior due to muscle problems.
Dani Carvajal and Eder Militao are ruled out for the season with anterior cruciate ligament injuries, while David Alaba is not expected to return from his long-term absence until the beginning of 2025.
Los Blancos are hopeful that Aurelien Tchouameni will be ready to return to the matchday squad following a spell on the sidelines.
Bellingham is expected to fit for Wednesday's away trip despite being forced off at half time of Sunday's win over Getafe due to a neck issue.
Athletic Bilbao possible starting lineup:
Agirrezabala; De Marcos, Vivian, Alvarez, Berchiche; Ruiz de Galarreta, Prados; I. Williams, Sancet, N. Williams; Djalo
Real Madrid possible starting lineup:
Courtois; Vazquez, Asencio, Rudiger, Garcia; Modric, Valverde, Bellingham, Guler; Rodrygo, Mbappe
We say: Athletic Bilbao 2-2 Real Madrid
Real Madrid may have won their last three league games against Osasuna, Leganes and Getafe, but they will face a much tougher test in Wednesday's tricky away meeting with Athletic.