La Roja's starting XI is sure to be much different to that which lined up against Albania earlier this week, after head coach Luis de la Fuente rested several key players - making a total of 10 changes.
Only Aymeric Laporte was retained, and the Al-Nassr centre-back must now hope to resume his partnership with another France-born defender, Robin Le Normand.
Nacho may be passed fit following a muscular injury, so it remains to be seen how the Spanish rearguard will be composed - though Dani Carvajal and Marc Cucurella are both expected to play at full-back.
Manchester City midfielder Rodri is back from suspension and should be joined by Fabian Ruiz and Pedri in the Spanish engine room, where the latter would make a record fourth appearance in the European Championship knockout phase before reaching the age of 22.
Dani Olmo laid on the only goal against Albania, which was scored by Barcelona's Ferran Torres after just 13 minutes; however, both are set to be demoted to the bench this weekend, alongside centre-forward Joselu.
Instead, captain Alvaro Morata - who netted a hat-trick against Georgia in qualifying - should be flanked by Lamine Yamal and Nico Williams, who both completed at least five dribbles and created more than four chances across Spain's group matches.
Finally, Arsenal's David Raya will make way for 2019 European Under-21 Championship winner Unai Simon in goal.
Spain possible starting lineup: Simon; Carvajal, Le Normand, Laporte, Cucurella; Pedri, Rodri, Ruiz; Yamal, Morata, Williams