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.
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.
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.
