The Brazilian visitors finished top of their group to advance, while Cali dropped into the second-tier competition after being eliminated from the Copa Libertadores.
Match preview
Tuesday's clash will be the first time that Cali have been in competitive action since May as the Categoria Primera A season takes a pause between its first and second stage.
The Red Devils finished eighth in the Torneo Apertura standings, seeing them narrowly scrape into the knockout phase.
However, they lost on aggregate to Millonarios in the quarter-finals, a result that saw a change in the dugout as Juan Carlos Osorio was brought on board.
First up for Osorio is this big clash with Paranaense, who have played 14 times since their opponents' last outing.
The Hurricane have won won eight and lost just two of those 14 matches, highlighting the size of the challenge America de Cali face in midweek.
Indeed, Athletico are fourth in the Brasileiro standings after drawing 2-2 with erstwhile leaders Bragantino at the weekend.
Antonio Oliveira's side have experience of winning the Sudamericana, too, having lifted the trophy in 2018.
America de Cali have never prevailed on the continental stage, meanwhile, though they have finished as Libertadores runners-up on four occasions, most recently in 1996.
America de Cali form (all competitions):
Athletico Paranaense Copa Sudamericana form:
Athletico Paranaense form (all competitions):
Team News
Paranaense will be without Santos and Abner Vinicius as they are away on Olympics duty with Brazil for the next month or so.
Lucas Halter is also expected to miss out for the visitors through injury.
As for the home side, they have added seven new faces to their squad, the most recent of which being Mauricio Gomez.
Osorio is expected to include two new signings - Jorge Segura and Elvis Mosquera - in his first starting lineup as Cali boss.
A 4-3-1-2 formation is likely, which would see Joao Rodriguez playing just off Jeison Lucumi and Adrian Ramos.
America de Cali possible starting lineup:
Graterol; Arrieta, Segura, Torres, Mosquera; Urena, Paz, Moreno; Rodriguez; Lucumi, Ramos
Athletico Paranaense possible starting lineup:
Bento; Marcinho, Ivaldo, Heleno, Nicolas; Richard, Christian; Nikao, Terans, Vitinho; Babi
We say: America de Cali 0-2 Athletico Paranaense
Paranaense eased through the group stage with five wins from their six group matches and have been in great form domestically, too.
The 2018 Sudamericana champions should prove too strong against an America de Cali side perhaps rusty after a more than two-month break between matches.