Isco was named in the starting XI for Real Madrid and Gareth Bale on a bench that also includes Karim Benzema and Toni Kroos for Saturday's LaLiga game against Levante.
Midfielder Isco makes his first appearance since a 1-0 win over Espanyol in September as Madrid look to end a four-match run in all competitions without a win.
They have failed to score during that disappointing stretch too, yet under-pressure boss Julen Lopetegui has opted to leave both Kroos and Benzema out of his starting XI.
Bale is also named as a substitute, the forward fit to feature after going off with a groin injury during his side's 1-0 loss to Deportivo Alaves prior to the international break.
The 29-year-old missed Wales' games against Spain and the Republic of Ireland but returned to training with Los Blancos this week.
Mariano Diaz starts in attack as Madrid look to revive their title challenge with the Clasico against Barcelona to come next Sunday.