Ronaldo opened the scoring in the sixth minute when a pinpoint cross from João Cancelo found him inside the box.
The Portuguese captain timed his run perfectly and finished with a clinical right-footed strike from close range, making it 1-0.
The goal also saw Ronaldo become the first player in football history to score in six different FIFA World Cups.
Second goal seals dominant first-half display
Ronaldo doubled his tally in the 39th minute after receiving a precise pass from Bruno Fernandes.
The veteran forward controlled the ball with ease before calmly slotting a right-footed shot inside the near post, beating the goalkeeper to make it 3-0 for Portugal before halftime.
Portugal continued to dominate after the break, eventually securing a comprehensive 5-0 win.
Ronaldo surpasses Eusébio's record
The brace helped Ronaldo overtake Portuguese legend Eusébio as Portugal's all-time leading goalscorer in FIFA World Cup history.
The performance also extended his remarkable record as the first footballer to score in six World Cup tournaments.
VAR denies Uzbekistan a consolation goal
Uzbekistan's best chance—and arguably their most heartbreaking moment—came when midfielder Azizjon Gʻaniyev unleashed a stunning long-range strike that found the net, briefly sparking celebrations among the Uzbek players and fans.
However, the goal was ruled out following a VAR review, which detected a foul on Portugal defender João Cancelo in the build-up to the move.
The decision denied Uzbekistan what would have been a memorable consolation goal on an otherwise difficult night against one of the tournament favourites.