Head coach Luis de la Fuente must tinker with a settled - and successful - side, as Pedri limped off with a knee injury last time out, and two members of La Roja's back four face suspension.
Sent off against Germany, Dani Carvajal joins centre-back Robin Le Normand on the sidelines, so De la Fuente may turn to a couple of experienced reserves to help keep Kylian Mbappe and co at bay.
Carvjal's former Real Madrid teammate Nacho should come in for Le Normand - who misses out on a meeting with the nation of his birth - while 38-year-old Jesus Navas is expected to fill the void at right-back.
Having scored as substitutes in the previous round, Dani Olmo and Mikel Merino will vie to replace Pedri in midfield, with either starting alongside Fabian Ruiz and the irreplaceable Rodri.
In attack, captain Alvaro Morata is flanked by in-demand Nico Williams and teenage star Lamine Yamal, who add pace and verve to a superb passing side.
Ferran Torres and Joselu have been regularly used as impact subs so far at these finals, and both can expect to see some second-half action once again.
Spain possible starting lineup: Simon: Navas, Nacho, Laporte, Cucurella; Olmo, Rodri, Ruiz: Yamal, Morata, Williams