Argentine forward Cesar Carranza broke the deadlock when he hooked in Luis Figueroa's cross in the 57th minute of the Group One match in Santiago.
Defender Roberto Cereceda added the second four minutes later in a move that he started and finished himself, and Lucas Barrios latched onto Rodrigo Millar's pass to slot home the third in the 65th minute.
Colo Colo went top of the group with six points from three games, ahead of Brazil's Sport Recife, who have a game in hand, on goal difference.
LDU, who last year became the first Ecuadorean side to win the trophy, are third with three points from three games.
LDU have lost three key players -- midfielder Enrique Vera and strikers Luis Bolanos and Joffre Guerron -- as well as coach Edgardo Bauza from last year's team.
Pedro Garcia scored twice in eight minutes in the second half to give Peruvian champions Deportivo San Martin a 2-1 win at home to Paraguayans Nacional in Group Three.
Garcia scored after Gonzalo Ludena broke from the halfway line in the 52nd minute and headed in from another chance created by Luduena on the hour.
Heber Arriola pulled one back for the visitors in the 71st minute.
San Martin, who pulled off a shock win over Argentina's River Plate last week, went level on six points with Uruguay's Nacional, who lead on goal difference.
Paraguay's Nacional are bottom of the group after losing all three games. River Plate, who started as favourites to win the group, have three points.
