Barcelona midfielder Pedri was a particularly crucial player at Euro 2020 at the age of 18, and Rodri will likely come into the middle alongside Serio Busquets and Koke in his absence.
Thiago Alcantara, Fabian Ruiz and Diego Llorente have also missed out on the squad, while Braga forward Abel Ruiz is a somewhat surprising call-up.
Ferran Torres should feature heavily in the front line, having already been clinical for the national team while also impressing in the early stages of the Premier League season for Manchester City.
Striker Alvaro Morata also boasts an impressive international record, having hit 22 goals in 46 caps.
At the other end of the pitch, Aymeric Laporte recently declared for Spain, and he should be joined by former Manchester City teammate Eric Garcia at the heart of the back four in the absence of Pau Torres.
Behind them, Unai Simon was chosen as the first-choice goalkeeper at Euro 2020, but Luis Enrique could use this opportunity to hand a first cap to Robert Sanchez, who earned his place in the squad for the European Championships with a strong run of form for Brighton & Hove Albion.
Spain possible starting lineup: Sanchez; Azpilicueta, Laporte, Garcia, Gaya; Busquets, Koke, Rodri; Torres, Morata, Moreno