Argentina qualified for the 2022 FIFA World Cup after defeating rivals Uruguay 1-0 at Estadio Campeón del Siglo in the early hours of Saturday morning.
Messi started from the bench as Argentina named two changes from their last match in Paulo Dybala and Guido Rodriguez, while Uruguay missed Federico Valverde and Edinson Cavani.
The Albiceleste grabbed the front foot on seven minutes after Angel Di Maria collected a lay off from Dybala to curl into the top corner of Fernando Muslera's net.
Uruguay nearly had the leveller just after the half-hour mark as a loose ball outside the area landed at the grasp of Luis Suarez, who volleyed off the top of the crossbar.
More chances continued to fall for the host minutes inside halftime with Matias Vecino's low shot from a promising area off a pass by Suarez working Emiliano Martinez to a clever save.
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As Joaquin Correa came on for the visitors and Uruguay introducing Facundo Torres, the host missed another opening following halftime after Joaquin Piquerez dragged a close-range chance wide.
Then a free-kick deep in his own half by Piquerez a little thereafter nearly led to the equaliser unfortunately though Martinez rushed off his line to smother.
Argentina decided to hand Messi a run out for the last 14 minutes as the renowned footballer came on in the place of Giovani Lo Celso.
This didn't stop the host carving out chances after a ball into the area from Piquerez saw Agustin Alvarez head over the top with five minutes remaining.
Messi managed to see possession at the death from a pass by Marcos Acuna and drilled over the top from outside the area, as it finished 1-0 to the Albiceleste who qualified for the World Cup finals.