Edinson Cavani produced the most impressive global performance of his career with two stunning goals to send Uruguay into the World Cup quarterfinals -but a second-half calf injury against Portugal has now left the Paris Saint-Germain striker facing a battle to be fit for Friday's last-eight matchup against France.
Argentina's hopes of going one step better than a narrow defeat to Germany in the 2014 final were ended by a 4-3 loss to Les Bleus, with Ronaldo quickly following Messi out of the tournament.
Cavani then had to be helped off by Ronaldo before watching the rest of the game from the dugout with ice on a calf injury.
Pepe's header was the first goal that Uruguay had conceded at this World Cup, but Oscar Tabarez's side recovered to secure a date with France in Nizhny Novgorod on Friday.
Uruguay took seven minutes to regain the lead as Cavani completed his brace.
Cristiano Ronaldo became the second big name player to crash out of the World Cup today after Portugal were beaten 2-1 by Uruguay.
European champions Portugal came up against a superior version of themselves as they were knocked out of the World Cup by Uruguay on Saturday. Uruguay, meanwhile, had not conceded a goal in 2018 - an impressive run of six games, three of them at Russian Federation 2018.
The highlights of Uruguay's pulsating win will show Suarez's superb assist for Cavani's opener, but his all-round play was just as key.More news: North and South Korea begin consultations on linking their motor roads - Yonhap
Cavani sent the ball across the field to Suarez, who aggressively dribbled to the top corner of the penalty area.
Taking to Twitter after the game, one viewer said: "Ronaldo just said F*** YOU to a referee".
However, they were unconvincing in 1-0 wins over Egypt and Saudi Arabia, before upping their game for an impressive 3-0 victory over hosts Russian Federation in their final group match.
Goalkeeper Fernando Muslera did nearly gift them another equaliser, dropping a high ball at the feet of Bernardo Silva, but the Manchester City man could only volley over.
Ronaldo had an opportunity around the half-hour mark to score from a free kick 30 metres out but could only hit the wall.
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.
Uruguay: Muslera 7, Gimenez 8, Godin 8, Laxalt 7, Caceres 6, Bentancur 6, Nandez 6, Torreira 6, Vecino 6, Suarez 8, Cavani 9.
Portugal have now lost their last four World Cup matches in the knockout stages of the tournament, since a goalless draw with England in the 2006 quarterfinals. But with Uruguay sitting back, Portugal did equalise 10 minutes into the second half.