The Portuguese scored a late penalty as Los Blancos progressed to the semi-finals of the Champions League with a 4-3 aggregate win over Juventus last Wednesday, with Madrid having previously surrended their three-goal lead from the first leg.
He was then rested for the weekend win away to Malaga, where goals from Isco and Casemiro saw Real secure a 2-1 victory which lifted them back up to third place in the table, but he should return for this one.
Madrid have no game this weekend because they were due to face Sevilla and the Andalusians are in action in the Copa del Rey final against Barcerlona on Saturday. But here, Goal takes a look at everything you need to know ahead Wednesday's match at the Bernabeu...
Real Madrid injuries
Nacho is still sidelined for Real, but the defender will be back soon from what is the first injury of his entire career and Zidane has an otherwise full-strength squad from which to choose on Wednesday.
Real Madrid suspensions
Sergio Ramos was suspended for the Champions League clash against Juventus last week, but Madrid have no players banned for this match.
Real Madrid potential starting line-up
Ronaldo is set to return in attack along with Gareth Bale after both were rested for the game against Malaga on Sunday, with Karim Benzema dropping to the bench this time.
In defence, Marcelo and Raphael Varane are also likely to be back in the line-up after Theo Hernandez and Jesus Vallejo featured from the outset at La Rosaleda.
Isco should keep his place after his impressive performance in the south of Spain, where he notched a goal and an assist against his former club.
Athletic Club team news
This has been a poor season for Athletic Club and the Basque outfit are down in 13th place with just 39 points with six rounds of La Liga remaining.
After the summer departure of coach Ernesto Valverde to Barcelona, his replacement Jose Angel Ziganda has been unable to get the team challenging for a European place, something to which the club has become accustomed in recent seasons.
Following an impressive 3-1 win at Villarreal in their last away game, Athletic slipped to a miserable 3-2 loss at home to struggling Deportivo La Coruna at the weekend.
Defender Xabier Etxeita is doubtful for Wednesday's game in an otherwise full-strength squad for Ziganda.
TV channel & kick-off time
Real Madrid versus Athletic kicks off at 21:30 local time on Wednesday and will be shown live in the United Kingdom (UK) on Sky Sports Football from 20:25 GMT.
In the United States (US) , the match is live on beIN Sports and kicks off at 15:30 ET.
Best Opta match facts
Real Madrid have failed to win in 11 different games at the Santiago Bernabeu in all competitions this season (drawn six, lost five), their worst figure in a single campaign since 1999-00 (14).
However, Los Blancos are unbeaten in their last six La Liga home games (won five, drawn one), scoring 26 goals in the process (4.3 per game on average).
Athletic have won 39 points from their 32 La Liga games this season – their worst return at this stage of a season since 2012-13 (36 points).
Gareth Bale has been involved in at least one Real Madrid goal in his last three league appearances (three goals and one assist).
Cristiano Ronaldo has scored 16 goals in his 17 league appearances against Athletic, but he has failed to score in his last three games against the Basques.