It was the biggest defeat ever for Croatia, which was playing its first competitive game since reaching the World Cup final in Russian Federation.
Spain started the second half with the same intensity as they had in the first half, and it didn't take them long to score.
He promised evolution, not revolution, and while his team still dominated possession, they were faster, more direct and less predictable in the final third.
The hosts soon increased their lead with two thumping strikes from Marco Asensio, the second of which was given as an own goal to Croatia goalkeeper Lovre Kalinic as it bounced off him after crashing against the crossbar.
Spain and Croatia go head to head in England's group, and World Cup bronze medallists Belgium get their UEFA Nations League campaign underway, all live on Sky Sports on Tuesday night. Saul and Asensio cut through Croatia's medium block with two precise passes, which left Rodrigo Moreno in an easy 1v1 to make it 4-0.
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After this game, Croatia will host England in their next Nations League match on Friday 12 October.
Lukaku made it 2-0 to Belgium minutes later, firing a close-range shot on the rebound that was judged to have crossed the line before Birkir Saevardsson managed to clear.
After beating England 2-1 in manager Luis Enrique's first game in charge, the new-look La Roja stunned their European counterparts at the Estadio Manuel Martínez Valero.
The Croats were making their Nations League debut after playing European champion Portugal to a 1-1 draw in a friendly last week.
The visitors actually started brightly and the story of the match could have been very different had they taken one of three golden opportunities inside the opening 20 minutes. They replaced Marcos Alonso, Thiago Alcantara and Iago Aspas.
Belgium striker Romelu Lukaku scored twice and won a penalty that Eden Hazard converted as they crushed Iceland 3-0 in their Nations League A, Group 2 clash in Reykjavik on Tuesday.