Estudiantes, champions in 2009, thumped Guarani of Paraguay, helped by a hat-trick of headers from Rodrigo Lopez.
LDU, winners in 2008 and the only Ecuadorean club to have won South American's equivalent of the Champions League, routed five-times former champions Penarol 5-0 in Quito.
Colombia's Atletico Junior beat Oriente Petrolero 2-1 to qualify for the last sixteen and Peruvian champions Leon de Huanuco drew 1-1 with Brazilians Gremio.
In La Plata, Lopez, who won the Libertadores with Olimpia in 2002, scored twice in the first 20 minutes to set Estudiantes on their way before Leandro Gonzalez added the third in the 25th minute, again from a header.
Despite have defender Facundo Roncaglia sent off for elbowing in the 51st minute, Estudiantes continued to dominate.
Uruguayan Lopez completed his hat-trick just before the hour and Gonzalez notched his second, while Julian Benitez scored the Paraguayan's consolation goal in between.
The Argentineans, who have nine points, moved one behind Group Seven leaders Cruzeiro with both teams looking set to qualify.
In high altitude Quito, Walter Calderon scored twice as LDU demolished once-mighty Penarol of Uruguay.
Carlos Luna and Hernan Barco were also on target, while Carlos Suarez put through his own goal and Fabian Estoyanoff missed a late penalty for the visitors.
The result left Group Eight wide open with LDU, Godoy Cruz and Penarol on six points each and Independiente on three.
In steamy Barranquilla, Group Two leaders Atletico Junior notched their fourth straight 2-1 win thanks to two goals in eight minutes from Carlos Bacca to qualify with two games to spare and leave their Bolivian opponents pointless.
The Colombians are five points clear of Gremio, who should join them in the last sixteen after former Porto midfielder Carlos Alberto scored early in the second half to give them a 1-1 draw in Peru.
Carlos Elias had put the Peruvians ahead just before half-time.
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