In last week's first round first leg, a blistering strike from Gualberto Mojica gave Oriente a 1-0 victory at home in Bolivia.
Oriente will head to Montevideo on Tuesday knowing a 2-1 loss would be enough for them to advance at the expense of Nacional.
It would be a huge shock for Nacional - perennial challengers for South America's premier continental club competition.
Nacional have won the Copa Libertadores three times (1971, 1980, 1988), while they made the semi-finals as recently as 2009, but having qualified as Uruguay's third-best team this year, they were forced into a play-off to earn a spot in the group stage.
In their favour will be a strong crowd at the Estadio Gran Parque Central in Montevideo, while they have warmed up with a 2-0 triumph over local rivals Racing on Saturday in their opening match of the Uruguayan Primera Division's Clausura championship.
Coach Gerardo Pelusso was still able to rest key players such as Richard Porta, Ivan Alonso and Pablo Alvarez.
Porta will be one of Pelusso's main weapons up front against Oriente, while Nacional can also call upon the impressive talents of veteran playmaker Alvaro Recoba with the former Inter man still a handy option off the bench with his wicked left foot.
Argentina's Lanus are in the best position to advance of the 12 teams involved in the Copa Libertadores' first round.
The reigning Copa Sudamericana champions won 2-0 over Caracas in Venezuela thanks to a brace from Paolo Goltz.
In all the other ties, just a single goal separates the two teams.
Colombia's Santa Fe and Atletico Paranaense of Brazil will head home with some confidence after managing away goals in their respective 2-1 losses to Liga MX outfit Morelia and Sporting Cristal of Peru.
Ecuador's Deportivo Quito must travel to Brazil with a 1-0 advantage over Botafogo, while Chile's Universidad de Chile is in the same position ahead of their trip to Paraguay to play Guarani.
