Ronaldo got the ball rolling early on with a tap-in, before further goals from Joao Felix and Bernardo Silva made it 3-0 inside 18 minutes, while Ronaldo added another just after the half-hour mark.
Second-half goals from substitutes Otavio and Rafael Leao completed another routine victory for Portugal after its 4-0 win over Liechtenstein to kick off qualifying campaign and the rein of new coach Roberto Martinez.
Portugal sits top of Group J after two games, two points ahead of Slovakia in second after its win against Bosnia-Herzegovina.
Portugal took the lead in the ninth minute when a ball to the far post from Bruno Fernandes was headed back across goal by Nuno Mendes, giving Ronaldo a simple tap-in from close range.
The advantage was doubled just six minutes later, as this time Silva's in-swinging ball from the right was nodded across Luxembourg goalkeeper Anthony Moris and into the corner of the net by Joao Felix.
Silva got on the end of a long pass from Joao Palhinha to head in the third, while Ronaldo grabbed his second and Portugal's fourth in the 31st minute when Fernandes played him through on goal, with the Al Nassr striker placing his left-foot shot low to Moris' right.
Portugal had another in the 77th minute when Leao and Otavio combined, with the latter heading home the Milan attacker's cross from the left.
Leao saw a late penalty saved by Moris after winning it himself, but made up for it shortly after when his run inside from the left ended with a composed finish.