Dagoberto, Leo Lima and Washington scored the goals in a 25-minute spell spanning half time to leave Sao Paulo top of Group Two with nine points from four matches, a point ahead of Colombia's Once Caldas.
Mexico's Monterrey, held 2-2 at home by Once Caldas in the early hours of Thursday morning, are third with five points. Paraguayan champions Nacional have no points.
Sao Paulo, who had beaten Nacional 2-0 in their previous group match in Asuncion, went ahead after half an hour.
Dagoberto, lurking beyond the left post, rose to a right cross from midfielder Hernanes to send a looping header that dipped inside the top far corner of the net.
Leo Lima tapped in the second three minutes later and Washington scored the third nine minutes after half time when the ball ran loose after keeper German Caffa blocked Richarlyson's run into the box.
Internacional, the last Brazilian side to win the trophy in 2006, were held 0-0 by Uruguay's Cerro in a Group Five match played in the Uruguayan city of Rivera.
About 20,000 Inter fans crossed the border from the southern Brazilian city of Porto Alegre to boost the crowd at the Atilio Paiva stadium to around 28,000 but ended up jeering Inter's Uruguayan coach Jorge Fossati.
Cerro lead the group with seven points, two more than Inter, after three matches. Ecuadorean champions Deportivo Quito have one point and Emelec, also from Ecuador, none after two games.
Uruguay's Racing drew 0-0 at Colombian champions Independiente Medellin, who had two payers sent off, to remain in second place in Group One.
Racing are three points behind one of the title favourites, Corinthians of Brazil, after three matches. Medellin are a point further back.
Striker Cesar Valoyes was sent off in the 66th minute for a second yellow card offence and substitute Lewis Ochoa was dismissed for diving, also a second booking, one minute from time.
