Julio Vaccari's side sealed a second-placed finish in Group C to book their place in the knockout rounds, while the visitors comfortably topped Group F.
Match preview
The last-16 curse has bedevilled Velez Sarsfield during their three most recent stints in the pinnacle of South American football, and Vaccari's outfit will not expect to be heading into their next battle at this stage of the Copa Libertadores as favourites.
The hosts won two, drew two and lost two of their six group matches to just about hold off the threat of Uruguayan outfit Nacional and advance to the knockout rounds, which was sealed on the sixth matchday courtesy of an eye-catching 4-0 success over group winners Estudiantes.
However, Vaccari's side have only managed one win in four Argentina Primera Division matches since advancing to the last-16 of the Copa Libertadores, where they were knocked out by Barcelona SC in the 2021 edition, and not since 2012 have the one-time champions progressed further.
Velez were forced to settle for a point in a 1-1 draw with Defensa y Justicia away from home over the weekend, with Nicolas Garayalde's 90th-minute effort cancelling out Nicolas Fernandez's 88th-minute opener, and drab goalless affairs do not come naturally to the hosts, who were both the highest scorers (12) and leakiest defenders (11) in their Copa Libertadores group.
As expected, River Plate's run to the Copa Libertadores knockout rounds was smooth sailing, as the four-time champions scored 18 goals, conceded three and dropped just two points en route to the next stage of the tournament.
Marcelo Gallardo's outfit were one of only three sides to make it through to the last-16 without losing a game, alongside Palmeiras and Flamengo, while conceding just a trio of goals represents the joint-best defensive record in the competition so far.
Back-to-back wins in the Argentine top flight was just what the doctor ordered before Wednesday's showdown for River Plate, who edged past River Lanus 2-1 at the weekend and finished the game two men to the good as Lanus saw Matias Perez and Braian Aguirre expelled in the dying embers.
There was a somewhat alarming shortage of goals in the River Plate camp after the conclusion of their Copa Libertadores group stage, which ended with Julian Alvarez scoring six of his side's eight goals in an 8-1 thumping Club Alianza Lima, but the soon-to-be Manchester City man has helped them rediscover their golden touch at just the right time.
River Plate - who last lifted the Copa Libertadores trophy in 2018 - have made a recent habit of winning one then losing one against Velez Sarsfield, but their most recent encounter ended in a comfortable 2-0 success for the visitors back in August.
Velez Sarsfield Copa Libertadores form:
Velez Sarsfield form (all competitions):
River Plate Copa Libertadores form:
River Plate form (all competitions):
Team News
Velez Sarsfield recently bolstered their defence with the signing of former Atletico Madrid centre-back Diego Godin, but the 36-year-old needs time to build up his fitness and may not be ready for the first leg.
Fellow centre-back and captain Lautaro Giannetti is a long-term absentee with his cruciate ligament rupture, but the hosts are otherwise well-stocked for Wednesday's battle, where Garayalde will expect to displace Agustin Mulet in the first XI.
It would be a surprise to see Vaccari make any alterations to the side that thumped Estudiantes 4-0 in their most recent continental match, as Lucas Pratto wears the armband up front once again.
Meanwhile, River Plate lost midfielder Nicolas de la Cruz to a knock in the first half against Lanus, but Gallardo played down the severity of the issue after the game, and he could still make the squad for Wednesday.
Santiago Simon is on standby should De la Cruz not make the cut, while Robert Rojas, Matias Suarez, Milton Casco and Felipe Biafore also occupy spots in the infirmary.
Elias Gomez should continue to fill in for the stricken Casco at left-back, as Alvarez aims to build on his magnificent six-goal haul from his side's final group game.
Velez Sarsfield possible starting lineup:
Hoyos; Guidara, De los Santos, Gomez, Ortega; Garayalde, Perrone, Sonora; Orellano, Pratto, Janson
River Plate possible starting lineup:
Armani; Mammana, Diaz, Martinez, Gomez; Perez, Fernandez, Paradela; Simon, Alvarez, Barco
We say: Velez Sarsfield 1-3 River Plate
Goals should be on the menu between two Argentinian outfits who always know how to find the back of the net, although the River Plate defence is far more steadfast than Velez's.