Rafael Farfan put Huancayo ahead in the first minute of the second half, but the Ecuadorian side managed to turn things around with goals from Paraguayan forward Fernando Gimenez (59), Miller Bolanos (60) and Marcos Caicedo (83).
Gustavo Quinteros' team are now in a comfortable position ahead of the second leg, to be played next Wednesday in Guayaquil.
Chilean giants Colo Colo claimed a 1-0 win at Uruguayan side El Tanque Sisley thanks to a 26th minute goal from Argentinian forward Javier Toledo.
Colo Colo coach Gustavo Benitez said: "Winning is very important and we have a useful advantage ahead of the second leg - but nothing is defined because this is only the first half of a long match."
River Plate of Uruguay also celebrated abroad as they beat Blooming 1-0 in Bolivia.
The match did not start well for River as Sebastian Taborda missed a penalty in the second minute, but Michael Santos gave his team the win with a 58th minute goal.
Blooming defender Julio Moreyra will miss the return match on August 7 in Montevideo as he was sent off five minutes from time.
Colombian side Pasto are the only team who managed a home win on the second matchday of this year's tournament, seeing off Peru's Melgar 3-0.
Pasto led 3-0 inside 26 minutes thanks to two goals by defender Nicolas Palacios and one from Luis Murillo. A bad night for the visitors was capped two minutes from time by the dismissal of defender Victor Balda.
In Chile, Universidad Catolica and Paraguay's Cerro Porteno drew 1-1. The visitors led thanks to a 31st-minute header by midfielder Matias Corujo - but Catolica captain Cristian Alvarez headed a 70th minute equaliser.