Brian Montenegro and Derlis Orue scored either side of half-time as Nacional claimed a two-goal aggregate lead after the first leg of their Libertadores semi-final against Defensor.
While Nacional had to survive a late barrage from their Uruguayan visitors, clearing a shot off the line in second-half stoppage time, the Paraguayan Division Profesional club held on for a vital victory.
The hosts hit the front 10 minutes before half-time with Montenegro starting and finishing the move.
The 21-year-old striker gathered possession around 25 yards from goal, played a square pass to Julian Benitez, who returned the ball with a chip over the top, and Montenegro thrashed the ball across Defensor's goalkeeper Martin Campana into the far corner of the net.
Nacional doubled their lead in the 70th minute when their corner was partially cleared by the visitors only for Orue to volley back through a crowd of players to score.
After Orue scored the home side's second goal, Defensor took over, hitting four shots to one but failing to break down Nacional's defence.
Nacional are looking to become just the second Paraguayan club to reach the final of the Copa Libertadores after three-times champions Olimpia, who lost the 2013 final to Brazil's Atletico Mineiro.
Defensor Sporting have never reached the final of South America's premier continental club competition either and will have to come from behind in their home leg of the semi-final, which will be held on July 29.