Angel Di Maria, Gabriel Mercardo and Sergio Aguero scored but it was not enough as Lionel Messi and his teammate crashed out of the tournament.
It was two weeks ago that Ronaldo scored a hat-trick in the same stadium against Spain, stroking his chin after the first goal to imply he was the "greatest of all time".
"It's not the time to talk about the future of the coach, the players, the squad", he said.
"Our next game is in five days which is not a lot of time, but after today we will rest". We gave our best. "The team played well".
But then who is Edinson Cavani? He was helped to the sideline with his arm around Ronaldo's back.
Uruguay coach Oscar Tabarez said he was "worried" for the Paris Saint-Germain star while BBC pundit Martin Keown described Cavani being hurt as a "national disaster".
Cavani hobbled off with 16 minutes left with a suspected hamstring injury but is hopeful he will be fit in time to face France on Friday in Nizhny Novgorod.
Prior to the World Cup, Ronaldo led Real Madrid to a third-straight Champions League title but he arrived in Russian Federation surrounded by distractions about his club future and a tax fraud accusation back in Madrid. "A group that has a big ambition to triumph and that is why I am happy about everything".
Portugal's 63-year-old coach Santos said his team's talisman should continue.
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There is always competition to earn a place in the team, but things are easier "when they have given you the rules and everything is done based on our sacred word. which is respect". "Usually we also score".
There was promise for Portugal when Silva threaded intelligent balls into the penalty area, but the threat was quickly snuffed out with the Atletico Madrid pair of Jose Gimenez and Diego Godin commanding.
But Ronaldo will have a discussion on that topic for another day.
"The greatest virtue of the Uruguay team is that they are Uruguay".
Parity was short-lived, though, as Uruguay reclaimed the lead just seven minutes later.
And he managed to score a-not-too-shabby four games in the tournament.
What stood out Saturday against Portugal was Uruguay's comfort without the ball.
It was a five-pass buildup from deep in its own end that culminated in Uruguay's first goal, and the final two passes were flawless.
Cavani received the ball from Rodrigo Betancur and sprayed a wonderful 40-yard diagonal pass to Luis Suarez. Just a few steps inside Portugal's half, Cavani hit Suarez with a pinpoint cross over the top of the back line, and immediately made a run behind the Portuguese defense.