Santiago in Chile was the location for the first leg of the quarter-final tie and Luiz Felipe Scolari's Brazilian visitor Palmeiras left with two priceless away goals thanks to Bruno Henrique and Dudu.
Chilean giant Colo Colo made a nightmare start, conceding after just three minutes at Estadio Monumental David Arellano.
Moises squared the ball to Bruno Henrique, who curled his shot past Colo Colo goalkeeper Agustin Orion.
Dudu doubled Palmeiras' lead with 12 minutes remaining when he was on hand to tuck away the rebound after Willian's effort was pushed onto the post by Orion.
Palmeiras will host Colo Colo in the return leg in early October.