The Colombian team won for the first time in their last three matches on Sunday, beating Deportes Tolima 2-0, while El Ciclon lost 3-0 to Libertad in the Paraguayan Primera Division.
Los Diablos Rojos are in the group stage of this competition for a second consecutive season after failing to qualify for this tournament over their previous 10 attempts.
In the 2020 Copa Libertadores, the Colombians started slowly losing their first two games, which ultimately cost them a chance to progress into the knockout stage finishing at the bottom of their group and two points off second place.
Under new manager Juan Cruz Real, America de Cali have improved at home, winning two of their last three league fixtures, their only two home victories this year.
Winning back-to-back league titles should instill some confidence in this team that were runners-up in this competition for three consecutive seasons between 1985 and 1987.
Cerro Porteno are back in the group stage of this tournament after losing to Ecuadorian side Barcelona SC in the third round of qualifying last year.
The team based out of Obrero in Asuncion hope to recapture their magic from the 2019 tournament when they made it all the way to the quarter-finals before losing to River Plate.
In his second stint with the club, Francisco Arce will try to get this side back into form like they were in 2013, when he guided them to the Torneo Clausura title, going undefeated in the process.
The man known as "Chiqui" has a wealth of experience and success as a player, having featured in two World Cups for Paraguay and also winning this competition on two separate occasions.
Commonly known as "The People's Team", Cerro Porteno have progressed beyond the group stage of this tournament in each of their last two appearances in 2018 and 2019.
America de Cali Categoria Primera A form:
Cerro Porteno Paraguayan Primera Division form:
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Defender Kevin Andrade was sent off in the final minute of his team's 2-0 win over Deportes Tolima.
Leading goalscorer Santiago Moreno will be eager to get his name on the scoresheet, having gone without a goal in his last four league games, while goalkeeper Joel Graterol has clean sheets in his last two fixtures.
There are no injury concerns for Francisco Arce as they prepare to play in the group stage of this competition for the first time since 2019.
America de Cali possible starting lineup:
Graterol; Arrieta, Torres, Ortiz, Cabezas; Mosquera, Carrascal, Cabrera; Moreno, Abonia, Vergara
Cerro Porteno possible starting lineup:
Munoz; Espinola, Patino, Duarte, Arzamendia; Rojas, Cardozo, Villasanti, Aquino; Morales, Boselli
We say: America de Cali 1-1 Cerro Porteno
America are the best defensive team in Colombia right now, conceding only 12 goals in their first 18 matches, and they will aim for a better to start this tournament than they had in 2020.
Cerro Porteno have two incredibly potent strikers that know how to find the back of the net, so shutting them down for 90 minutes might be too much to ask.