Portugal's talisman Cristiano Ronaldo missed out following a foot injury, as Joao Felix got a look in along with Bruno Fernandes while the Croats travelled without Luka Modric and Ivan Rakitic.
The Portuguese were denied the lead in the opening 25 minutes as a double save from Croatia goalkeeper Dominik Livakovic denied Pepe from a corner-kick.
Portugal continued to dominate minutes later when a header from Diogo Jota came off the upright following Fernandes' back-post delivery, whilst Felix fired into the side-netting afterwards.
The frustrations weren't over for the Portuguese as Raphael Guerreiro curled onto the left-hand post from outside the area after 33 minutes with Livakovic helping the follow-up for a corner.
Livakovic was finally breached eight minutes later when Joao Cancelo darted across the edge of the area to arrow into the top-hand corner.
There weren't any changes from either side following halftime, whilst Fernandes' shot over the top following a free-kick metres outside the area.
Portugal evidently extended their advantage two minutes later after Jota showed up at the far side of the area to find the far corner following a deft finish.
The Croats shifted focus to the bench following the closing quarter, and in came Ivan Perisic and Marcelo Brozovic in place of Mario Pasalic and Josip Brekalo.
That did nothing to stop the Portuguese adding to their dominance on 70 minutes after Felix fired through Livakovic and into the roof of the net to put his side in cruise control.
Croatia grinded out a consolation in stoppage time after a spate of passes near the area released Bruno Petkovic, who beat Anthony Lopes from close-range.
The Portuguese restored their three-goal cushion with the last kick of the game after Andre Silva helped Pepe's glancing header into the near corner to wrap up the clash.