The Uruguay outfit began their Group Five campaign with a loss at Universidad Chile, and had to arrest an early deficit in Montevideo to take all three points against Garcilaso.
The Peruvians opened the scoring at the Estadio Centenario in sloppy fashion, making the most of some calamitous defending from the hosts.
Edwin Retamoso won a 50-50 ball in his own box, laid a ball back for Alfredo Ramua, and his on-target shot was clumsily fumbled into the net by Defensor goalkeeper Martin Campana.
Nicolas Correa then scored an equaliser for Defensor on 36 minutes, as he fired home the remnants of a saved free-kick.
After the sides were evenly matched at 1-1 at half-time, the second half belonged to Nicolas Olivera.
Olivera's through ball to Felipe Conceicao in the first minute after the re-start saw the latter finish confidently to put Defensor 2-1 up.
Then a late brace from the Uruguayan forward sealed the comprehensive result - Olivera's first goal the product of a ravishing Defensor counter-attack, before he lashed home a second with four minutes of regulation time to play.
In Group Three, O'Higgins moved top with a 1-0 win at home to Colombian side Deportivo Cali.
Yerko Opazo's 83rd-minute goal in Santiago de Chile was all that separated the two sides, with the Chilean outfit unbeaten in two matches.
Bolivar and Leon played out a 1-1 draw, to leave the latter first in Group Seven.
Leon struck first away in La Paz, as Mauro Boselli hit a deflected long-range strike past Bolivar custodian Romel Quinonez.
The hosts, though, earned a point as Juan Callejon got the slightest of touches on a cross in from Walter Flores - enough to deceive Leon shot-stopper William Yarbrough.
Leon were then presented with the chance to take all three points from Bolivia but Rafael Marquez's penalty was saved by a diving Quinonez - who kept out the solidly struck spot-kick with a double-handed parry to his right.
