Cazorla required numerous operations on knee, foot and ankle injuries that began in 2013, while an aggressive infection in his heel needed a skin graft, extracted from his left forearm.
Told he was lucky to walk again and could have lost his leg, Cazorla chose not to retire, instead moving to Villarreal from Arsenal last year and starting an incredible recovery.
The 34-year-old's call-up comes after he has been one of Villarreal's stand-out players this season, helping them avoid relegation with four goals and 10 assists in 34 appearances. He has only missed three league matches.
Cazorla will now hope to feature in Spain's upcoming European Championship qualifiers against the Faroe Islands on June 7 and Sweden on June 10.
The midfielder's last international appearance came when he scored in a 2-0 friendly win over England in November 2015.
Coach Luis Enrique was unable to attend the squad announcement at Las Rozas on Friday due to the same personal problems that prevented him taking charge of Spain's last fixture against Malta.
His assistant Robert Moreno oversaw the release of the list, which included recalls for Real Madrid's Isco, who was left out in March, and Real Sociedad striker Mikel Oyarzabal, who was last selected in May 2016.
Dani Carvajal, Diego Llorente and Iago Aspas also returned.
Juan Bernat, Sergi Gomez, Dani Ceballos, Sergio Canales, Iker Muniain and Jaime Mata all dropped out, after being selected in the previous squad.
Squad
Goalkeepers: David de Gea (Manchester United), Kepa Arrizabalaga (Chelsea) and Pau Lopez (Betis)
Defenders: Dani Carvajal (Real Madrid), Sergio Ramos (Real Madrid), Mario Hermoso (Espanyol), Diego Llorente (Real Sociedad), Inigo Martínez (Athletic Bilbao), Jordi Alba (Barcelona), Sergi Roberto (Barcelona), Jose Gaya (Valencia), Jesus Navas (Sevilla)
Midfielders: Sergio Busquets (Barcelona), Rodrigo Hernandez (Atletico Madrid), Dani Parejo (Valencia), Isco (Real Madrid), Fabian Ruiz (Napoli), Santi Cazorla (Villarreal)
Forwards: Mikel Oyarzabal (Real Sociedad), Rodrigo Moreno (Valencia), Marco Asensio (Real Madrid), Iago Aspas (Celta), Alvaro Morata (Atletico Madrid)
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