Dropped: Florian Wirtz
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The £125million British record signing has missed the last three games across all competitions after suffering a groin injury against Eintracht Frankfurt two weeks ago, and was absent from training on Monday afternoon.
Hugo Ekitike will continue to lead the line in Isak's absence, and did score in the Reds' last Champions League outing against former club Frankfurt.
Elsewhere, Ryan Gravenberch is also back in contention after returning from an ankle injury in the much-needed 2-0 win over Aston Villa. Curtis Jones was able to join his team-mates at Melwood on Monday, but remains a doubt to face the Spanish giants.
Arne Slot has a decision to make over Florian Wirtz and Milos Kerkez, two summer signings who have endured miserable starts to life at Anfield. The pair were dropped for the win over Villa and face fights to start against Madrid.
Alisson Becker, Jeremie Frimpong and Giovanni Leoni remain sidelined for the foreseeable.
Doubts: Jones
Injured: Isak, Alisson, Frimpong, Leoni
Time and date: 8pm GMT on Tuesday, November 4, 2025
How to watch: Amazon Prime
Venue: Anfield