La Banda picked up a valuable 1-1 draw in the first leg against Los Albos at Estadio Monumental David Arellano last Tuesday.
Match preview
River Plate extended their unbeaten run in the current Libertadores campaign after leaving Chile with a draw last Tuesday, in a game that saw eight yellow cards and two red cards - one each for both sides.
La Banda took the lead just before the break when German Pezzella found the net, but Carlos Palacios restored parity for Colo-Colo just after the hour mark.
River Plate have yet to lose when scoring the opening goal in the Libertadores, dropping points in only one instance in that scenario (2-2 draw versus Nacional).
Marcelo Gallardo, who has won the Copa Libertadores titles twice with the Argentine side, in 2015 and 2018, reached a milestone of 100 matches as a coach in the competition, the third-highest, only behind Luis Cubilla (104) and Gabriel Uribe (116).
River Plate are unbeaten across all competitions in their previous 10 games, picking up a 1-0 win in the Argentine Primera Division against Boca Juniors in the Superclasico last Saturday in their most recent game.
La Banda, who are unbeaten at home against Wednesday's visitors in this competition, winning 4-0 the last time out in 2022, will hope to replicate this result and make it to the semifinals of this competition for the first time since 2020.
Meanwhile, Colo-Colo are still looking to win their first quarter-final match in this competition for the first time since defeating Universidad Catolica 3-1 in 1997.
However, they have won just one of their four away games in the Libertadores this season - a 2-1 victory over Junior FC in the round of 16 - which is their most recent one.
After losing an away game against Fluminense on 10 April, Jorge Almiron's men went unbeaten on the road for five months, stretching for 13 matches, until a 3-0 loss to Magallanes in their Chilean cup which is their most recent away game.
On Tuesday, Eterno Campeon are in danger of failing to win in three competitive matches for the first time since April of this year (three).
River Plate Copa Libertadores form:
D
W
W
W
W
D
River Plate form (all competitions):
W
D
D
W
D
W
Colo-Colo Copa Libertadores form:
L
D
D
W
W
D
Team News
River Plate will enter this clash without Rodrigo Aliendro, who is nursing a shoulder injury that is likely to keep him out until late October.
Pity Martinez is also unavailable due to a cruciate ligament tear until next month, while Maximiliano Meza is carrying a knock that could sideline him for the next few days.
Paulo Diaz, one of the two players who were sent off in the first leg draw, will be suspended for the second leg.
Colo-Colo will continue to be without Chilean midfielder Vicente Pizarro, who is recovering from a broken jaw with no definitive return date yet, and Cesar Fuentes, who suffered a cruciate ligament tear in March.
Maximiliano Falcon, who was also sent off in the first leg, is suspended for Wednesday's clash.
River Plate possible starting lineup:
Armani; Bustos, Pezzella, Acuna, E. Diaz; Simon, Fernandez, Kranevitter; Echeverri, Borja, Meza
Colo-Colo possible starting lineup:
Cortes; Isla, Amor, Saldivia, Wiemberg; Gil, Pavez; Vidal, Palacios, Cepeda; Correa