Messi, who had dramatically announced the end of his international career in June following Argentina's Copa America Centenario final defeat to Chile, scored via a deflected shot in the 42nd minute to spark wild celebrations in Mendoza's Estadio Malvinas.
The victory – the first under the reign of new coach Edgardo Bauza – catapulted Argentina into first place in South America's marathon round-robin qualifying campaign with 14 points after seven games.
But Argentina was made to work hard for the victory, playing the second half with only 10 men after young Juventus striker Paulo Dybala was sent off just before halftime after a second yellow card. Dybala was led off the field in tears following the dismissal.
Uruguay had named a powerful looking starting line-up, with Messi's Barcelona teammate Luis Suarez spearheading the visitors' attack alongside Edinson Cavani. Captain Diego Godin was also back in the heart of the Uruguayan defence to give the two-time World Cup winners a reassuring solidity.
Yet with the talismanic Messi back in the fold, it was Argentina who enjoyed the better of the opening half.
Angel Di Maria created the first chance after 32 minutes, winning the ball brilliantly in midfield before laying off to Dybala who advanced on goal.
