Atletico Nacional hammered last year's runners-up Penarol 4-0 away in Montevideo to take control of Group 8.
Jherson Cordoba opened the Colombian champions account in the 9th minute with a beautifully angled shot past Fabian Carini.
Just after the break, the deadly striker doubled his tally and Atletico's advantage with a clinical half-volley from close range.
In the 64th minute, Dorlan Pabon raced clear of Penarol's poorly constructed offside trap to make it 3-0, before grabbing his brace 13 minutes later with a powerful drive from the edge of the box.
At the Estadio Hernando Siles in La Paz, Union Espanola of Chile came from a goal behind to beat Bolivar 3-1.
Edhemir Rodriguez put the Bolivians ahead with a 1st minute tap-in, before Mauro Diaz, Emanuel Herrera and Jean Paul Pineda overturned the deficit in the second-half for Union, who remain top of Group 3 with maximum points from their opening two games.
In Group 4, Argentina's Arsenal reacted positively to their opening defeat against Fluminense by thrashing Zamora 3-0 in Sarandi. El Viaducto secured the points courtesy of first-half goals from Jorge Ortiz(1'), Carlos Carbonero(15') and Luciano Leguizamon(43').
Finally, Cruz Azul made it two wins from two with a straightforward 4-0 victory over Deportivo Tachira. Adrian Cortes, Edixon Perea, Javier Orozco Penuelas and Emanuel Villa were on the scoresheet for Los Cementeros in Mexico City.
Last night's results:
Bolivar 1-3 Union Espanola (Group 3)
Arsenal de Sarandi 3-0 Zamora (Group 4)
Cruz Azul 4-0 Deportivo Tachira (Group 6)
Penarol 0-4 Atletico Nacional (Group 8)
Tonight's fixtures:
Velez Sarsfield v Chivas Guadalajara (Group 7)
Universidad de Chile v Godoy Cruz de Mendoza (Group 8)
