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.
Croatia, for whom Ivan Rakitic was making his 100th appearance, rarely got to grips with their opponents and conceded three times more in the second half through Rodrigo Moreno, Sergio Ramos and Isco.
Spain will host Croatia at Elche's Estadio Manuel Martinez Valero on Tuesday as the UEFA Nations League competition continues.
In the World Cup final, Vicente del Bosque put out six Barcelona players (Puyol, Pique, Busquets, Xavi, Iniesta and Pedro) along with Villa who had just signed from Valencia.
"It's a great challenge to play against Luka in the Spanish league and it's even better to play with him for our country", Rakitic said.
The UEFA Nation's League match between Spain and Croatia will be broadcast live on ESPN2 and Univision Deportes. But Spain weren't finished, 8 minutes later, Serjio Ramos scored the 5th from a corner kick.
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.
Iceland manager Erik Hamren has now lost his opening two games as manager, conceding nine goals in the process, leaving the Nordic nation's reputation for a miserly defence in tatters. During the Russia World Cup, they were the most represented club with six players.
Isco capped Spain's offensive show with a right-footed shot from the center of the box in the 70th minute.