Zinedine Zidane’s side sit second in Group B behind Borussia Monchengladbach, following one win and one draw from their opening three games.
Their coming Italian foes sit two points below them at the bottom of the group, with just two points to show from their opening three fixtures.
Antonio Conte’s hopes of picking up his first win in the Champions League this season will be boosted by the return of Belgian striker Romelu Lukaku, who missed the reverse fixture earlier in the season when Madrid won the tie 3-2.
Lautaro Martinez is also expected to return to the side in place of Alexis Sanchez, despite the Chilean’s goal and assist in Inter’s 4-2 win over Torino at the weekend.
However, Conte will be without Marcelo Brozovic and Aleksandar Kolarov if they end up returning another positive COVID test.
Another bonus for the hosts will be the fact that Madrid travel to Italy without essential central defender Sergio Ramos and striker Karim Benzema.
Both players missed Madrid's draw with Villarreal at the weekend and while Benzema was expected to return for the Champions League clash he has since been confirmed as out of action.
Zidane will also be without Serbian forward Luka Jovic, after the player returned a positive COVID test.
Some good news for the Madrid manager will come in the form of defensive midfielder Casemiro returning to the starting XI, following his rest at the weekend.
As well as the return of Martin Odegaard, Dani Carvajal and Eden Hazard in recent weeks.