Real Madrid confirmed defender Nacho Fernandez has suffered a ligament injury to his right knee in the 4-2 win at Celta Vigo on Sunday, while Casemiro sprained his right ankle.
The club have not provided a timetable for the recovery of either player but reports in Spain suggest Nacho is facing two months out and Casemiro will be sidelined for a minimum of three weeks.
Casemiro was unable to see out the first half, while Nacho was replaced by Marco Asensio in the 71st minute with at Balaidos.
The loss of another defender will be a blow for interim head coach Santiago Solari, with Marcelo, Raphael Varane, Dani Carvajal and Jesus Vallejo still out of commission.
However, Solari will hope to have Isco back to full fitness after he underwent an operation to treat acute appendicitis in September.
Madrid return to action when they travel to Eibar in LaLiga on November 24.