A 1-1 draw in the second leg at the Estadio Ciudad de Lanus in Argentina was enough for Paraguayans Cerro Porteno, who booked their spot in the last eight courtesy of a 3-2 win on aggregate.
Oscar Romero opened the scoring for Cerro Porteno in the opening minute before Diego Braghieri levelled proceedings in the 39th minute.
But the draw was not sufficient enough for the Primera Division high-flyers to continue their title defence.
Cerro Porteno - league leaders in the Division Profesional - went into the return leg protecting a 2-1 lead.
The Paraguayan giants also boasted a 10-game unbeaten streak in all competitions and that showed as they took a first-minute lead.
Romero, who inspired Cerro Porteno to victory in the opening leg with his second-half brace, dispossessed his opponent outside the area and curled the ball past Lanus goalkeeper Agustin Marchesin.
But Lanus - second in Argentina's top flight behind River Plate - got themselves back into the contest six minutes before half-time.
Defender Braghieri was the unlikely goalscorer following a sensational solo effort that saw him receive the ball on the halfway line and beat four defenders before looping the ball over Marchesin from an acute angel.
Cerro Porteno will face either two-time champions Boca Junior or Deportivo Capiata in the quarters.
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