Diego Doldan inspired the first-leg win, setting up Pedro Chavez and Blas Caceres as Paraguayan side General Diaz netted two priceless away goals at the Estadio Atanasio Girardot in Medellin.
General Diaz's triumph on the road ended their 20-game winless streak away from home in all competitions.
Their most recent away win came in October, when they beat Libertad 3-0 in the Division Profesional.
In the midst of a four-game unbeaten run after Sunday's 2-2 draw at home to Boyaca Chico, Colombian Primera A giants Nacional were expected to earn something from the fixture.
But Juan Carlos Osorio's men were left licking their wounds as the visitors scored two unanswered goals in a nine-minute period.
Veteran midfielder Chavez opened the scoring in the 17th minute, bustling his way between opponents and playing a one-two with Doldan on the edge of the area before placing the ball beyond Nacional goalkeeper Franco Armani.
Nacional had a golden opportunity to level proceedings seven minutes later after referee Juan Soto awarded a penalty, but Edwin Cardona's spot-kick hit the post.
The home side were made to pay as General Diaz doubled their lead in the 26th minute, when Caceres took the ball off the feet of team-mate Doldan and volleyed powerful into the bottom corner.