However, defeat for the Argentine giants would let in their opponents, who are one point adrift of the Group D leaders, and Atletico Junior.
Match preview
With 20 players testing positive for coronavirus and no goalkeepers at their disposal, River Plate looked to be on a hiding to nothing ahead of their fixture with Sante Fe.
However, Marcelo Gallardo's side pulled off one of the great results in this competition's history, scoring twice in the first six minutes before holding on for a 2-1 victory with midfielder Enzo Perez between the sticks.
While it remains to be seen whether Los Millonarios will be boosted by the return of several key players, Gallardo will be delighted to see any one of the 20 squad members become available for this contest.
Although their form should not be taken into consideration ahead of this contest, River Plate have only prevailed in three of their last nine fixtures in all competitions.
Despite not enjoying his best season on the domestic scene, two of Julian Alvarez's four goals have come in this tournament.
As far as Fluminense are concerned, their surprise defeat at home to Atletico Junior has put what seemed to be a likely place in the last 16 under threat.
With Atletico Junior possessing a better head-to-head record, only success at Estadio Monumental Antonio Vespucio Liberti will guarantee their place in the knockout stages.
Roger Machado's team had been on an 11-match unbeaten streak, but they have now suffered successive defeats for the first time since the start of March.
Fluminense have also gone 10 matches without keeping a clean sheet, something which may need to change if they are to make further progress.
River Plate Copa Libertadores form:
River Plate form (all competitions):
Fluminense Copa Libertadores form:
Fluminense form (all competitions):
Team News
With only a five-day gap between the Santa Fe fixture and this one, Gallardo may find himself having to select a similar River Plate XI.
Perez will naturally return to an outfield position if a goalkeeper is able to feature, but Gallardo may be prepared to stick with the same team.
However, he will be desperate for players to fill the substitutes' bench after having no replacements available last time out.
Meanwhile, Machado will consider making several changes to his Fluminense side after their recent performances.
Youngster Kayky could be kept on the right flank, but Nene may be preferred to Juan Cazares in the number 10 role.
Abel Hernandez will also expect to replace Fred in attack after scoring as a substitute against Atletico Junior.
River Plate possible starting lineup:
Perez; Lecanda, Maidana, Martinez; Casco, Carrascal, Pena, Paradela, Angileri; Alvarez, Montana
Fluminense possible starting lineup:
Felipe; Calegari, Nino, Claro, Barcelos; Felipe, Martinelli; Kayky, Nene, Henrique; Hernandez
We say: River Plate 1-1 Fluminense
Given everything at stake on Tuesday evening, this fixture is a difficult one to call. Nevertheless, River Plate have made a habit of claiming draws in this group, and we see no reason to back against them recording another against Fluminense.