Key La Roja duo Rodri and Dani Carvajal are ruled out for several months with ACL injuries, while Robin Le Normand - who would have been suspended for this match anyway - suffered a 'traumatic brain injury' while representing Atletico Madrid earlier this month.
Barcelona trio Dani Olmo, Ferran Torres and Gavi are also sidelined with injuries, along with Athletic Bilbao's Nico Williams and Girona's Bryan Gil.
Luis de la Fuente is therefore enforced to make changes to the starting lineup that began the 4-1 win against Switzerland last month, with Pedro Porro and Oscar Mingueza set to battle for a start at right-back in Carvajal's absence.
Seventeen-year-old starlet Pau Cubarsi could be handed just his second senior international start in central defence alongside Aymeric Laporte, while Marc Cucurella should get the nod over Alex Grimaldo to play at left-back.
In the absence of Rodri, in-demand Real Sociedad star Martin Zubimendi could be tasked with operating as Spain's midfield anchor, and he could be joined in the middle of the pitch by Pedri and Fabian Ruiz, the latter of whom scored twice against Switzerland last time out.
Captain Alvaro Morata is expected to earn his 81st cap and start as the central striker, while Barcelona sensation Lamine Yamal and Villarreal's Alex Baena could be called upon to provide support in attack from the flanks.
Spain possible starting lineup: Raya; Porro, Cubarsi, Laporte, Cucurella; Pedri, Zubimendi, Ruiz; Yamal, Morata, Baena
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