The South Americans began the tournament with an uneventful goalless draw against South Korea, where neither side could register a shot on target.
Having progressed from the group stage in each of the last three World Cups, Uruguay will look to give their chances of reaching the last 16 a boost with a win against Uruguay.
Here, Sports Mole looks at three reasons why Uruguay will be confident of claiming a victory over Portugal.
Record against European opponents
Since experiencing a poor run of two victories in 25 games against European nations at the World Cup, Uruguay have experienced an upturn in fortunes.
They have won four of their last five meetings with European opponents, although the only defeat in that period took place against France in the 2018 quarter-finals.
Before they lost 2-0 to France, they had enjoyed a run of four consecutive World Cup victories against European sides, and their last win against such opposition came against Portugal four years ago.
Cavani netted a brace on that occasion to secure a 2-1 victory in the last 16, and Uruguay will be looking to replicate that result on Monday.
Portugal's South American struggles
For Portugal, the defeat to Uruguay in 2018 highlighted their struggles against South American opponents, with the Selecao finding wins hard to come by.
In their last nine games against South American countries across all internationals, Portugal have won once, drawn three times, and lost on five occasions.
Their only win in that period took place in a friendly with Argentina in 2014, where Raphael Guerreiro scored a stoppage-time winner to clinch a 1-0 victory.
Portugal's two World Cup meetings with South American opposition in the 21st century resulted in a goalless draw against Brazil in 2010 and the 2-1 defeat to Monday's opponents four years ago, which represents the only previous occasion the Selecao have ever faced Uruguay in the tournament's history.
Strong defence
As a result of playing out a goalless draw with South Korea in their opening game of the tournament, Uruguay have now kept a clean sheet in each of their last five World Cup group games.
They have the chance to write their names in the history books on Monday as no country has ever recorded six straight clean sheets in the group stages.
Their impressive defensive record has also been impressive throughout the current calendar after keeping eight clean sheets in the 10 internationals they have played in 2022.
Having only conceded two goals this year, Uruguay's resilient defence will certainly be put to the test against Portugal.
Read more on Portugal vs Uruguay
Click here to read our full preview for Portugal vs Uruguay
How Portugal could line up against Uruguay
How Uruguay could line up against Portugal
World Cup 2022: Reasons for Portugal to be confident of beating Uruguay