Croatia, whose side contained just four of those who started the World Cup final in Moscow this July - defender Domagoj Vida and midfielders Luka Modric, Ivan Rakitic and Ivan Perisic - had actually started the game the stronger but now have to regroup before facing England in October.
Croatia, so impressive in keeping the ball at the World Cup, lost confidence as Spain dominated possession and picked their opponents off easily, inflicting biggest defeat on the Croats after a 5-1 loss to England in a World Cup qualifier in 2009.
Marco Asensio was arguably the star of the show and scored his first global goal on 33 minutes by capitalising on some sloppy midfield play to collect the ball 25 yards out and beat Lovre Kalinic with a left-footed rocket.
Spain were in a confident mood after winning their first game under Luis Enrique 2-1 away to England in their Nations League opener on Saturday and once they scored the floodgates opened and Croatia were left chasing shadows. Two matches, two convincing wins against top opponents in the UEFA Nations League.
Spain's Saul Niguez celebrates after scoring his side's opening goal.
Croatia's biggest defeat had been a 5-1 away loss against England at Wembley in 2009. Croatia drew with Portugal in a friendly last week.
Spain's World Cup campaign ended in chaos and disappointment, as they lost to hosts Russia on penalties in the last 16 after coach Julen Lopetegui was sacked on the eve of the tournament for holding talks with Real Madrid without informing the Royal Spanish Football Federation (RFEF). Spain was coached by Fernando Hierro in Russian Federation after Julen Lopetegui was sacked two days before the tournament.
Marco Asensio scored once and set up four more in Luis Enrique's second match in charge, as the World Cup finalists were run ragged in Elche.