The outclassed Uzbeks, coached by the Italian 2006 World Cup winner Fabio Cannavaro, were perfect opponents for Ronaldo to rediscover his scoring boots.
It was 2-0 on 17 minutes when Mendes curled in a free-kick.
The Uzbeks thought they had pulled one back, after a screamer by Azizjon Ganiev, but the goal was ruled out after a VAR intervention for a foul on Cancelo.
It was Ronaldo’s day, and he rolled in a third with only the goalkeeper to beat with a smart, controlled finish.
He might have had a third following an intricate freekick routine, but Nematov denied him, clattering into the veteran attacker in the process.
From the resulting corner it was 4-0, with Ronaldo in the thick of it again before the ball went in off Nematov for an own goal.
Substitute Rafael Leao scored an emphatic fifth in the 87th minute.
Before this, the evidence against Ronaldo was beginning to stack up.
In the previous 10 games at major competitions (World Cup and Euros) before the Uzbekistan match, he had zero goals and one assist.
He did though have a successful season with Al Nassr in Saudi Arabia, scoring 28 goals in 30 league games.
Portugal’s final group match is on Saturday against Colombia, who beat the Uzbeks 3-1.
Colombia meet DR Congo later Tuesday in Group K knowing a win will propel them into the last 32.