The two sides, who have conceded a combined 15 goals in the group stages so far, played out a thrilling 4-4 draw in the reverse fixture last month.
Match preview
Atletico Nacional suffered their first defeat in this year's Copa Libertadores when they lost 2-0 at home to Argentinos Juniors last week.
A brace from Gabriel Avalos either side of half time helped the visitors secure all three points against the hosts, who played the final 20 minutes with 10 men as Emanuel Olivera was handed two yellow cards in the space of seven minutes.
Alexandre Guimaraes's side have claimed four points from their first three matches in Group F and are now five points behind El Bicho who sit at the summit.
Nacional have won the Copa Libertadores twice before, firstly in 1989 and more recently in 2016 beating Ecuadorian side Independiente del Valle 2-1 in the final.
Guimaraes will be hoping he can guide El Verde to another final this campaign and a victory on Wednesday would boost their chances of progressing to the knockout stages.
Nacional lost their second game in Group F last week when they were defeated 3-1 away at Universidad Catolica.
Leandro Fernandez equalised for the visitors in first-half stoppage time, cancelling out Fernando Zampedri's earlier penalty. However, the hosts came out on top in the second half as strikes from Diego Valencia and Clemente Montes secured all three points for the Chilean side.
Alejandro Capuccio's side now sit bottom of the group at the midway point, three points behind Wednesday's opponents Atletico, who currently occupy the second qualification spot.
Nacional's primary focus is on the Copa Libertadores as their Uruguayan Primeira Division campaign - which saw them seal their second consecutive top-flight title and the 48th in their history - finished in March.
The Uruguayan side have progressed to the knockout stages in five of the last six years, but suffering defeat in midweek would all but eliminate them from the competition.
Atletico Nacional Copa Libertadores form:
Atletico Nacional form (all competitions):
Nacional Copa Libertadores form:
Nacional form (all competitions):
Team News
Atletico Nacional centre-back Olivera is suspended so Yerson Mosquera is the most likely option to play alongside Geisson Perea.
Guimaraes is set to start with the same four attacking players that featured in last week's group match, which will likely see Baldomero Perlaza and Jarlan Barrera operate on the flanks, with playmaker Andres Andrade in behind striker Jefferson Duque.
As for Nacional, defender Christian Almeida is suspended but Guzman Corujo - who is back from his own one-game ban - is set to return to the starting lineup as a result.
Goalkeeper Guillermo Centurion was dropped to the bench last week, with Sergio Rochet starting in his place and the latter could keep his place in the side on Wednesday.
Gonzalo Bergessio, who scored a hat-trick in the 4-4 draw against Atletico last month, is expected to lead the line once again and the 36-year-old could be supported in attack by Fernandez.
Atletico Nacional possible starting lineup:
Quintana; Candelo, Mosquera, Perea, Banguero; Rovira, Londono; Perlaza, Andrade, Barrera; Duque
Nacional possible starting lineup:
Rochet; Laborda, Gabrielli, Almeida; Ocampo, Carballo, Toranza, Trasante, Candido; Fernandez, Bergessio
We say: Atletico Nacional 2-2 Nacional
Both defences have looked vulnerable throughout the group stages and goals are to be expected once again on Wednesday night.
With little to separate the two teams, another entertaining score draw could be on the cards at the Estadio Hernan Ramirez Villegas.