Guarani have been the form side of the competition so far this season but faced a stern test against a Libertad side who went into the round a game away from their top-of-the-table hosts.
In a frenetic start to the match between the cross-town rivals, Antonio Bareiro gave Libertad an instant lead in the opening minute before Luis Gonzalez levelled the scores just two minutes later.
Fernando Fernandez then made it 2-1 to Guarani in the 12th minute with Luis Gonzalez grabbing his second from the spot soon afterwards to put the home side well on top.
Two second-half goals saw Fernandez complete his hat-trick as Guarani romped home, ensuring they moved three points clear at the summit of the table.
Olimpia remain within striking distance thanks to their 1-0 home victory over bitter rivals Cerro Porteno in the Super Clasico.
Christian Ovelar finished off a well-rehearsed corner in the 26th minute with his header proving to be the difference between the two sides.
Cerro Porteno did find the back of the net soon after the goal through Mauricio Sperduti but it was ruled out for offside, with the away side unable to muster an answer as Olimpia earned bragging rights.
Rubio Nu got their first win of the Clausura season thanks to an emphatic 3-0 triumph against Deportivo Capiata.
Angel Lucena put the home side ahead in the 54th minute before Alejandro Da Silva scored two goals in five minutes to seal the win.
Sportivo Luqueno escaped with a 1-1 draw against General Diaz thanks to a late Luis Mino strike while 3 de Febrero and Sol de America shared the spoils after they drew 1-1.
The game between 12 de Octubre and Nacional Asuncion was postponed with the latter travelling to Austria for a friendly against a Paraguayan selection team on Wednesday.