The hosts are making their first appearance in the tournament since 2014, while the visitors have taken part in each of the last four years.
Velez Sarsfield have flown out of the blocks in their domestic endeavours, picking up 22 points from their first 10 matches.
This run of form has propelled Mauricio Pellegrino's men to the top of the standings with a six-point cushion over Boca Juniors.
In their last involvement in the competition, El Fortin reached the round of 16 seven years ago when they were eliminated by Nacional Asuncion.
The hosts have a chance to begin their cup run on a high as they go in search of their first continental crown since 1996.
Flamengo are one of the household names in the Copa Libertadores having previously won the tournament twice, most recently two years ago.
Rogerio Ceni's men came out victorious in the Brazilian Super Cup last Sunday when they defeated Palmeiras on penalties.
Since then, the Mengao have not won any of their subsequent two league games, but they are still in second place on the log.
In the meantime, the focus is now on starting their Copa journey with a bang as Wednesday's visitors look to make it into the knockout stages for the fifth year in a row.
Flamengo's Gabriel Barbosa was in inspiring form back in 2019 as his nine goals in 12 matches - including a two-goal haul in the final - propelled his side to glory.
Several players from that title-winning team are still around, and that experience could come in handy in the latter stages.
Juan Martin Lucero scored within 10 minutes of coming off the bench in his side's last match, and he could be rewarded with a start in this one.
Velez Sarsfield possible starting lineup:
Hoyos; Ortega, Abram, Gianetti, Guidara; Caseres, Mancuello, Almada; Orellano, Centurion, Tarragona
Flamengo possible starting lineup:
Alves; Luis, Caio, Arao, Isla; Gerson, Diego, Ribeiro, De Arrascaeta; Barbosa, Henrique
We say: Velez Sarsfield 0-2 Flamengo
Flamengo are the superior side in terms of squad quality, and we expect that gulf in class to translate into a victory for the visitors, but the hosts have shown enough to suggest that they will be no pushovers.