Uruguay had not conceded a goal in the tournament until a header from veteran central defender Pepe breached the defence of the South Americans.
Cavani scored a handsome second just past the hour mark, taking up a good position in the left channel before bending an exquisite first time strike into the right side of the net.
Sebastian Coates had started in his place and, had he started, Ronaldo would have relished the chance to play against him.
He was an ever present thorn in Portugal's backline with his height, physicality and technical ability allowing him to pose a threat in a number of different ways, creating a handful for the opposition to deal with.
It was Cavani who instead took the spotlight.
Remarkably, the pair pack their bags still never having scored in a World Cup knockout game.
"He is an exceptional player", said Uruguay's veteran coach Oscar Tabarez.
The 2018 FIFA World Cup kicked off on June 14 and will continue until July 15, with the matches being played in 11 cities across Russian Federation.
According to Federation Internationale de Football Association, at 31 he is the oldest Uruguayan to score a World Cup brace, 108 days older than Diego Forlan who scored twice against South Africa in 2010.
Ronaldo struck a hat-trick in his opening game - a thrilling 3-3 draw with Spain, including a brilliant late free-kick to level the match.
Meanwhile, Ronaldo did not touch the ball once in the opposition area in the first period.
This could be the end of Cristiano Ronaldo, who at 33, must know he cannot get his hands on the biggest football prize anymore and he still failed to score in the second round of the FIFA World Cup.
Star player Luis Suarez scored twice as Uruguay defeated Egypt, Saudi Arabia and hosts Russian Federation to set up a Round of 16 tie with reigning European champions, Portugal. Next up for the underdogs is France and if they can snatch the first goal, their defence could see them through to the final four. Uruguay's full-backs, Diego Laxalt at the left and Martin Caceres at the right, were alert in dealing with Guerreiro and Jao Mario on the left and Bernado and substitute Ricardo Quaresma on th right.
Ronaldo was unable to trouble Uruguay as they made it through to the quarter-final against France and, at 33, with a 154 caps to his name, this could represent a natural watershed.