Two first-half goals were enough for the home side Libertad to see off Itagui and hold the advantage in the two-legged final-eight clash.
Midfielder Oscar Molinas opened the scoring in the 39th minute after converting Brian Montenegro's assist.
It did not take long for the Paraguayans to strike again as Sergio Aquino provided Jorge Recalde with Libertad's second goal five minutes later.
In the day's other quarter-final, Argentina's Velez Sarsfield were held to a 0-0 draw with Brazil's Ponte Preta.
The second legs for both matches will be played on November 8.
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