The visitors, meanwhile, must win to have any chance of making it to the next stage of the competition.
Match preview
Having won the Copa Libertadores on four occasions in their history - most recently in 2015 and 2018 - River Plate will be expecting to compete at the business end of South America's primary continental competition once again.
However, falling to a defeat against their forthcoming opponents at Estadio Mas Monumental would see River Plate crash out at the group stages, with a draw only enough to get them through should Sporting Cristal fail to beat Fluminense in Group D's other final match.
Having won three successive league games to move 10 points clear at the top of the Argentinian Primera Division, head coach Martin Demichelis will be confident of his team getting the business done given their rich reign of form in recent times and billing as huge favourites.
Indeed, having won 20 of his 28 games in charge since taking over last November, the former Bayern Munich and Manchester City defender is a hugely popular figure at the club where he came through as a player before departing for Germany, and he can expect a raucous atmosphere supporting him and his players on Wednesday.
The Strongest, on the other hand, have recently changed managers after Ismael Rescalvo departed for Mexican side Mazatlan last month, with Claudio Biaggio returning in his place for his second spell in charge of the club.
Based in La Paz, the capital of Bolivia, only Bolivar have won more domestic titles in the country than The Strongest, whose most recent triumph in 2021 was their 15th in the club's history.
Despite appearing in the Copa Libertadores on 28 occasions, they have only managed to progress to the knockout stages twice since the turn of the century, when they were knocked out in the round-of-16 in 2014 and 2017.
As such, Wednesday's trip to Buenos Aires represents a huge opportunity for Biaggio and his players to cause an upset and create more history for the club that they proudly represent.
However, given that they currently lead their domestic division by a point, it will not be the be all and end all in terms of marking this season as a successful one or not, especially with most of their opponents in this competition much more heavily financially backed than them.
River Plate Copa Libertadores form:
L
W
L
D
W
River Plate form (all competitions):
D
D
W
W
W
W
The Strongest Copa Libertadores form:
W
L
L
W
L
The Strongest form (all competitions):
L
W
L
L
W
L
Team News
River Plate will remain without former Everton striker Salomon Rondon due to suspension after his dismissal against Sporting Cristal, while Bruno Zuculini is still out of action due to a serious knee injury.
Matias Suarez, David Martinez and Elias Lopez are also all major doubts, with Demichelis likely to call upon the services of his captain Enzo Perez for such a huge occasion.
The Strongest, meanwhile, may hand Junior Arias a start in attack after only utilising the 30-year-old from the substitutes' bench during their 6-3 defeat to Nacional Potosi at the weekend.
Biaggio may be concerned about his side's shambolic defensive display during the surprising loss, which saw their title rivals move one point behind them, but he is unlikely to make too many changes.
River Plate possible starting lineup:
Armani; Herrera, Pirez, Diaz, Casco; De La Cruz, Perez, Fernandez, Barco; Solari, Beltran
The Strongest possible starting lineup:
Viscarra; Torres, Castillo, Pedraza, Avellaneda; Carrasco, Quiroga; Isnaldo, Ortega, Franco; Arias
We say: River Plate 3-1 The Strongest
River Plate will be confident of securing their safe passage through to the knockout stages with a victory, and we expect them to do so given their superior individual ability.
The Strongest are regular qualifiers for the Copa Libertadores, but they rarely make it beyond the group stages, and we think that will be the case once again this season.