The former European and World Cup winners trained on Monday ahead of the game where they will be looking to build on their flawless start after beating England 2-1 on Saturday.
Sergio Ramos, one of the remaining members of Spain's golden generation, added the fifth goal with a header off a corner kick in the 57th minute, and Isco closed the scoring in the 70th after another set up by Asensio.
Spain were in dreamland two minutes later as Asensio cheekily lofted a shot from 20 yards that ricocheted off the crossbar, before deflecting in off goalkeeper Lovre Kalinic for the third goal.
Spain scored three goals in each half as they completely outplayed Croatia, who were playing just their second game since the World Cup final.
The two goals are his only two for Spain in 12 appearances to date.
AP Croatia midfielder Ivan Rakitic wasn't too happy with his team's performance against Spain
Croatia's biggest defeat had been a 5-1 away loss against England at Wembley in 2009.
Vrsaljko provided Ivan Perisic with another chance during Croatia's early barrage but Spain's own right-back came to the rescue as Dani Carvajal tracked the Inter Milan winger to make a crucial intervention 10 yards from goal.
In his press conference on Monday, Enrique said he made a mistake by not initially calling up Aspas for the UEFA Nations League fixtures against England and Croatia. Hamren made three changes to the side that lost to the Swiss with Runar Sigurjonsson, Emil Hallfredsson and Hordur Magnusson coming in for Rurik Gislason, Gudlaugur Victor Palsson and Bjorn Sigurdarson and his side looked much more stable in the opening exchanges.
Meanwhile, Zlatko Dalic offered fringe players Mateo Kovacic and Marko Pjaca opportunities to shine after their peripheral roles in their shock World Cup run.
In contrast the Belgians poured forward, with Thomas Meunier hitting the foot of the post midway through the second half, and Lukaku blazing a late shot over the bar before steering the ball past Halldorsson to complete the rout.More news: OnePlus 6T fingerprint on display confirmed