An 80th-minute goal from Julio Dos Santos was the difference as Porteno defeated 10-man Deportivo Cali 3-2 to finish top of the group, while Lanus' goalless draw at O'Higgins was enough to secure their passage to the next round.
Francisco Arce's Porteno topped the group on 10 points after six games, ahead of Lanus (eight).
O'Higgins and Cali both finished on seven points apiece.
Porteno, Lanus, O'Higgins and Cali were all in contention to progress to the next round of South America's continental competition heading into matchday six, with one point separating the four teams.
But it was Porteno and Lanus who booked their passage into the final stages.
Cali of Colombia made the perfect start against Porteno, taking a 12th-minute lead courtesy of Christian Marrugo at the Estadio General Pablo Rojas.
However, the Paraguayan club hit back to take a 2-1 lead into the half-time interval.
After some patient build-up play on the edge of the area, Porteno were back on level terms thanks to Cali defender Luis Payares, who sent the ball past his own goalkeeper on 37 minutes.
Porteno were ahead eight minutes later after former Spain international Daniel Guiza managed to find enough time and space to unleash a shot on target.
Carlos Rivas restored parity on the hour-mark but Dos Santos stepped up to convert a penalty with 10 minutes remaining following a handball inside the area.
There were no goals between Chile's O'Higgins and Lanus at the Estadio El Teniente, though it was still enough for the Argentine outfit.
Elsewhere on Tuesday, The Strongest joined Velez Sarsfield in the next round after edging Group 1 rivals Atletico Paranaense of Brazil.
Paranaense were two points ahead of The Strongest in second position and seemingly on track to qualify alongside leaders Sarsfield.
But an own goal from Manoel and a fortuitous chip from Nelvin Soliz saw the Bolivian team run out 2-1 winners on home soil to finish on 10 points, ahead of Paranaense (nine).
In the other Group 1 game, Sarsfield of Argentina won 1-0 at home to Peru's Universitario, who finished bottom with one point.
Sarsfield topped the group on 15 points, with five wins from six matches.
