Ernesto Valverde's side have found life tough in the early part of the new campaign, and will be seeking to stop the rot after three defeats in four domestic games so far this term.
Anyone who has seen Athletic play in the early stages of the new season will know that the San Mames club have been capable of both the sublime and the ridiculous.
Bilbao turned heads as they cut European champions Barcelona to ribbons in a 4-0 victory over Luis Enrique's side in the first leg of the Spanish Super Cup, but they then succumbed last weekend to a poor 3-1 defeat at the hands of Villarreal.
Despite showing glimpses of brilliance in that early cup game against Barcelona and their recent Europa League win over Augsburg, Bilbao have arguably struggled in the early stages of the new campaign.
After four La Liga fixtures, Valverde's charges have claimed just a solitary three points in a win over Getafe, while losing their other three league fixtures to Barcelona, Eibar and Villarreal.
What will please home fans going into Wednesday's clash is the current form of both Aritz Aduriz and Raul Garcia. As it stands, Adruiz has bagged nine goals in 10 games in all competitions this season and could pose a real threat to Madrid's defence.
One thing Bilbao will be aware of, however, is that they have the fourth poorest defensive record in the league and they could come under real threat from the likes of Cristiano Ronaldo and company. So far after four games, Athletic have conceded seven goals at an average of 1.75 per match.
The club's early-season form suggests that they could come into real trouble against Real, but given their Super Cup showing against Barcelona Valverde's men will know that they do have it in them to cause an upset.
Recent form (all competitions): LLWWL
Los Blancos come into Wednesday's encounter off the back of an unbeaten start to the new campaign, with Rafael Benitez's men winning three and drawing one in La Liga.
Madrid's defence have been particularly impressive so far and are yet to concede at all in the Spanish top flight, while in attack Real have bagged a standout 12 goals in four matches.
The two men at the forefront of Madrid's attacking success have been Ronaldo and Karim Benzema, who have each notched eight and four goals respectively in all competitions already this season.
Madrid have already been through a potentially slippery European test in the Champions League when they faced Shakhtar Donetsk last week, which they passed efficiently as Ronaldo scored a hat-trick as part of a 4-0 home win over the Ukrainian club.
In the league, Real come into this clash off the back of a rather laboured 1-0 victory over Getafe, having beaten Espanyol 6-0 away from home in the fixture beforehand.
Benitez has made two signings for the future in the shape of Danilo and Mateo Kovacic, and the club will be hoping that they can push ahead this season to give themselves some breathing space to enable them to introduce the two impressive talents more prominently in the latter stages of the season.
Real are yet to have really been dealt a proper challenge domestically thus far, but Wednesday's clash could put them under some pressure given the pace and high-pressing nature of Bilbao's attack.
Recent form (all competitions): WWWWD
Madrid have been dealt with a blow given that key centre-back Sergio Ramos has been ruled out after dislocating his shoulder against Shakhtar last week, meaning that Pepe could continue in defence alongside Raphael Varane.
Bilbao should be thrilled by the potential return of defensive midfielder Ander Iturraspe who has been out with a hamstring injury since July. The 26-year-old was fully back in training on Monday and could be pushing for a start come Wednesday night.
Athletic Bilbao possible starting lineup:
Iraizoz; Iraola, Laporte, Exteita, Balenziaga; Iturraspe, Rico; Gomez, Marcos, Susaeta; Aduriz
Real Madrid possible starting lineup:
Navas; Carvajal, Varane, Pepe, Marcelo; Modric, Kroos, Isco; Vazquez, Ronaldo, Benzema
Head To Head
The last fixture between the two clubs saw Athletic beat Madrid 1-0 at home last season, but Bilbao have not won consecutive games against Real in La Liga since 2005.
Madrid, however, have won three of their last five trips to Bilbao, with the other two fixtures ending in one draw and one loss at the old San Mame stadium. Madrid are yet to win a game at Athletic's new home.
We say: Athletic Bilbao 1-3 Real Madrid
Madrid will fancy themselves despite being away from home after producing some impressive showings both in defence and attack at the start of the new season. Athletic, meanwhile, have found things incredibly tough in La Liga and the visit of a frighteningly prolific Real attack could cause real problems for a side that has so far operated with one of the weakest defences in the league.