After an even match for a good part of the clash in Mendoza, goals from the Barcelona and Manchester City men sank the Celeste in the second half to keep the hosts top.
Sergio Aguero was the other man to get on the scoresheet in a brilliant second-half flurry, which puts the Albiceleste back at the top of CONMEBOL's World Cup qualifying competition at the halfway stage.
Argentina enjoyed a lion's share of possession during an entertaining first half in Mendoza, but struggled to break down a Uruguay unit which did not shy away from taking on their eternal rivals.
Just two minutes into the second period, Ezequiel Garay had a golden chance to put his team ahead. A looping free kick from Messi caught out the Uruguay defense, but the center back could only scoop his first-time effort over when the goal was gaping.
The Celeste were then somewhat lucky to keep all 11 men on the pitch; Diego Lugano invoked the home fans' fury with a vicious tackle on Romero, but was only shown the yellow.
With 20 minutes gone in the second half, the breakthrough finally arrived to the joy of the home fans. Patient build-up from Argentina left Di Maria with space on the edge of the area, but the Real Madrid star spurned the chance to shoot in favor of an intelligent pass poked home by captain Messi. Coach Alejandro Sabella leaped off the bench in delight, as the Ballon d'Or holder celebrated his 29th goal in international colors.
The game was decided shortly after with a team goal of clinical beauty. Aguero, Messi and Di Maria ripped the Uruguay defense to pieces on the break after a sloppy loss of possession, and it was again Angel's pass that was coolly tapped home by 'El Kun' to confirm the victory for the rampant Albiceleste.
And insult was added to injury for the Celeste with 10 minutes to go, courtesy of Messi who surgically placed a free kick under the wall and into the corner of the net to seal a 3-0 trouncing.
The win puts Argentina back to the top of its World Cup qualifying group with 17 points from its first eight matches, leading Ecuador and Colombia who also recorded victories on Friday. Uruguay, meanwhile, lies in fourth place just inside the group of teams that would earn automatic passage to Brazil 2014.
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