Luiz Felipe Scolari's Palmeiras reached the knockout phase with a 4-0 rout of Melgar, while San Lorenzo also progressed despite its 1-0 loss to Junior.
With one matchday remaining, Palmeiras has 12 points – two clear of second-placed San Lorenzo, which sits six points ahead of Melgar.
Palmeiras was too good for its Peruvian host in Arequipa, where attacker Gustavo Scarpa scored twice.
Gustavo Gomez – on loan from AC Milan – opened scoring with a strong header in the 10th minute and Scarpa's powerful effort doubled the lead 12 minutes later.
Scarpa made it 3-0 in the 67th minute and substitute Moises completed the scoring with nine minutes remaining, while Melgar's Carlos Neyra was sent off for a second yellow card in stoppage time.
Colombia's Junior won its first match of the campaign after edging its Argentinian visitor 1-0.
Meanwhile, 10-man Cerro Porteno – already assured of a spot in the last 16 – went down 2-1 at Zamora, which snapped a 17-game losing streak, in Group E.