Angel Di Maria was the difference away to rival Uruguay, his sublime seventh-minute strike lifting second-placed Argentina to victory.
Argentina, which tied its CONMEBOL FIFA World Cup qualifying record after going eight matches unbeaten on the road, is one win away from booking its spot at Qatar 2022 heading into Wednesday's (AEDT) showdown against Brazil, which qualified after its win over Colombia.
Lionel Scaloni's Argentina defeated Uruguay 3-0 during last month's international window, after La Celeste failed to make the most of its chances against the Copa America champion.
It was a similar story on home soil in Montevideo, where Uruguay lacked a cutting edge in front of goal, despite Luis Suarez's best efforts.
With Lionel Messi on the bench, Di Maria wore the captain's armband and Argentina's stand-in skipper broke the deadlock in the seventh minute.
Giovani Lo Celso won possession and laid the ball to Di Maria, who curled a stunning shot into the top corner of the net.
Uruguay continued to press numbers forward and had a chance to restore parity approaching half-time after Matias Vecino's brilliant turn created space for a shot, however it was easily dealt with by Emiliano Martinez.
Martinez was left scrambling as Facundo Torres's tricky cross almost looped over the Argentina goalkeeper before he palmed it behind for a corner in the 63rd minute.
As Uruguay pushed forward in search of an equaliser, it created more space for Argentina to attack and the visitors engineered a couple of decent openings before Messi was introduced off the bench during the closing stages.
With the minutes ticking down, an unmarked Agustin Alvarez headed over the bar for Uruguay, while Martinez almost saw the ball slip through his legs and into the net from a venomous Luis Suarez strike as the hosts' FIFA World Cup hopes remain in the balance.