Ronaldo, remarkably just one goal away from 100 for Portugal, was unavailable because of an infection in his toe believed to be caused by a bee sting, but the Selecao was flying at the Dragao despite the Juventus forward sitting in the stands.
Croatia's defensive third was a hive of activity throughout the first half as Portugal peppered the visitors' goal, hitting the woodwork three times before Joao Cancelo finally found a way through in spectacular fashion in the 41st minute.
Diogo Jota, one of those to hit the post in the first half, got a deserved goal – his first for Portugal – to double the hosts' advantage before the hour and Joao Felix added a third 20 minutes from time.
Bruno Petkovic's late consolation did little to take away from a routine win, which was wrapped up by Andre Silva in the final minute of injury time.
It did not take Portugal long to establish itself as the dominant force, but its quest to find the breakthrough was initially a frustrating one.
Cancelo, Bruno Fernandes and Joao Felix, who hit the post, had early opportunities, while Dominik Livakovic produced an unlikely double save to thwart Pepe.
Jota twice went close before the half-hour mark, first heading a Fernandes cross onto the upright and then lashing into the side netting after a promising run.
Croatia's luckiest escape came in the 33rd minute as Raphael Guerreiro's long-range strike hit the left-hand post, struck Livakovic's foot and bounced just wide.
But Portugal's persistence paid off just before half-time, Cancelo picking out the top-left corner from distance.
Jota made it 2-0 with 59 minutes on the clock, racing on to Guerreiro's lofted throughball and finishing neatly into the bottom-right corner after holding off Tin Jedvaj.
Joao Felix put Portugal out of sight 11 minutes later, his powerful low drive too hot for Livakovic to handle.
Croatia finally offered a modest attacking threat in the latter stages, pulling one back through a smart finish courtesy of substitute Bruno Petkovic.
But a Portugal victory was never in doubt and Silva restored the three-goal cushion with a close-range finish at the death.