Copa Libertadores champions River Plate won their first match in Group A, while Flamengo crushed San Jose 6-1.
After three consecutive draws, River defeated lowly Peruvian side Alianza Lima 3-0 on Thursday to move up to second in the group.
Goals from Matias Suarez, Lucas Martinez and Nicolas De La Cruz put Argentine giants River on track for the round of 16.
River's Suarez broke the deadlock after cutting insight his opponent and firing past Pedro Gallese in the 15th minute, with Lucas Pratto missing a penalty 10 minutes later.
Martinez doubled the lead within nine minutes of the second half in Buenos Aires before De La Cruz preserved River's unbeaten record in the 93rd minute.
Flamengo showed no mercy as they routed Bolivian visitors San Jose in Rio de Janeiro on Thursday.
Diego and Everton Ribeiro had given Flamengo a narrow 2-1 lead at half-time, but San Jose were blown away following the break.
Everton Ribeiro scored another, and Giorgian De Arrascaeta and Vitinho were on target, while Helmut Gutierrez turned the ball into his own net.
The humbling sent Brazil's Flamengo top of Group D, ahead of Penarol on goal difference, with San Jose languishing on a point.
Meanwhile, Freddy Vargas' 89th-minute equaliser salvaged a 2-2 draw for Deportivo Lara at Emelec in Group B.