An own goal by Argentina defender Leonardo Balerdi and a fortunate strike from Uruguay midfielder Maxi Araujo secured the victory, despite a second-half effort from Atletico Madrid striker Julian Alvarez.
Messi played his final match for Argentina in an emotional farewell friendly victory over Benin last month, bringing an illustrious international career spanning 207 appearances and 125 goals to an end.
Without the 39-year-old forward, Argentina struggled to break down a determined Uruguay side for much of Friday’s encounter.
Nico Paz came closest to opening the scoring in the first half, but his effort was comfortably saved by Uruguay goalkeeper Cristopher Fiermarin.
Uruguay took the lead shortly after the interval when a free-kick from Giorgian de Arrascaeta on the left caused confusion in the Argentine defence.
Manchester United defender Lisandro Martinez attempted to clear the delivery with a header, but his effort struck team-mate Balerdi and deflected into the net for an own goal.
De Arrascaeta was again instrumental seven minutes later, providing the corner that led to Uruguay’s second goal in the 53rd minute.
His delivery appeared to strike Araujo on the shoulder before looping over the goalkeeper and into the net.
Argentina responded through Alvarez, who reduced the deficit with a 73rd-minute strike to give his side hope of a comeback.
The striker had another opportunity to equalise in stoppage time, but Uruguay held firm to secure the 2-1 victory.
The result marked another positive outing for Forlan, who continued his promising start as Uruguay’s manager, while Argentina were left to reflect on their first outing in the post-Messi era.
