Portugal and Ronaldo were heavily criticised after an uninspiring 1-1 draw in their Group K opener against DR Congo, but they came alive under the roof at the Houston Stadium.
Nuno Mendes and Rafael Leao were also on target, while Uzbekistan conceded an own goal in a convincing performance by Roberto Martinez's side.
There had been much focus on Ronaldo's status in the team, but Martinez stuck with the 41-year-old on Tuesday (local time) and was rewarded with a determined display.
Ronaldo was eager to get off the mark after strong starts to the tournament by fellow world stars such as Lionel Messi, Kylian Mbappe, Harry Kane and Erling Haaland.
He needed six minutes to find the net, becoming the first player to score in six World Cups in the process.
He had already spurned one chance as he failed to connect with a brilliant cross from Mendes, but he made no mistake when he swivelled and fired in first time at the near post from a Joao Cancelo ball.
Mendes doubled the lead from a free-kick in the 17th minute. Uzbekistan feared a Ronaldo strike from the edge of the box, but the former Real Madrid star made only the slightest movement as Mendes drove home.
Uzbekistan, managed by Italy's 2006 World Cup-winning captain Fabio Cannavaro, thought they had pulled one back with a stunning strike from Azizjon Ganiev just before the half-hour. It was ruled out for a foul in the build-up.
Ronaldo compounded their frustration when he raced on to a well-weighted ball by Fernandes and finished coolly.
Ronaldo went close again just before the break as he just beat goalkeeper Abduvohid Nematov to the ball, but his chip was cleared off the line.
Portugal's fourth came on the hour when a low ball into the box took a series of deflections and ended up in the net after ricocheting off Abdukodir Khusanov and Nematov.
Leao completed the rout when he lashed into the roof of the net when a clearance rolled into his path.
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