The Brazilians defeated Universitario in the previous round, while Newell's OB received a bye after comfortably topping Group E.
Match preview
Corinthians, on the other hand, dropped down to South America's secondary competition after finishing behind Independiente del Valle and Argentinos Juniors in Group E of the Copa Libertadores.
Their head coach Vanderlei Luxemburgo will hope that a change of tournament leads to his side faring much better against different Argentinian opposition, with Corinthians aiming to win the Copa Sudamericana for the first time in the club's history.
The last five seasons have proven a particularly barren period for Timao, who since lifting their seventh domestic title in 2017 have failed to win any major silverware at all.
Having been knocked out of Brazil's domestic cup earlier in July, as well as trailing league leaders Botafogo by a whopping 21 points after just 16 matches, this competition remains their last chance of adding to their cabinet as far as this season goes.
Newell's OB, meanwhile, have not tasted success since winning their domestic division a decade ago. Moreover, they have never lifted any continental competition across their 120-year history.
Former Manchester United defender Gabriel Heinze has been in charge of them since last October, earning plenty of plaudits for guiding his side through to the knockout stages of this competition with a near-perfect record.
Indeed, after winning their first five matches in Group E, they missed out on perfection by only drawing a dead rubber against Audax Italiano, but they will take plenty of confidence from their strong performances overall when coming up against Corinthians across two legs.
Domestically, Heinze's side are occupying a mid-table position after 27 games, with their 1-1 draw against Talleres Cordoba summing up their general inconsistencies in the Argentine Primera Division.
Corinthians Copa Sudamericana form:
W
W
Corinthians form (all competitions):
W
W
W
W
D
W
Newell's Old Boys Copa Sudamericana form:
W
W
W
W
W
D
Newell's Old Boys form (all competitions):
D
L
W
D
L
D
Team News
Corinthians will remain without Rafael Ramos, Paulinho and Gustavo Silva due to long-term knee injuries, while Gabriel Moscardo is suffering with appendicitis.
Luxemburgo could make a few changes from the side which defeated Vasco de Gama 3-1 on Saturday, with Fausto Vera and Pedro providing two excellent options to come into the starting XI.
Newell's OB, meanwhile, will travel without Pablo Perez, Fabian Angel, Bruno Pitton, Francisco Gonzalez and Justo Giani due to injury problems.
Brian Aguirre was an unused substitute during his side's draw at the weekend, and Heinze may be tempted to restore the winger to the visitors' starting line-up.
Corinthians possible starting lineup:
Cassio; Mendez, Gil, Caetano, Santos; Vera, Maycon, Augusto; Pedro, Alberto, Guedes
Newell's Old Boys possible starting lineup:
Hoyos; Mendez, Velazquez, Glavinovich, Mansilla, Vangioni; Gomez, Sotelo, Montenegro; Aguirre, Reasco
We say: Corinthians 2-1 Newell's Old Boys
Corinthians have turned a corner in recent weeks, winning six of their last seven matches in all competitions, and we can envisage them extending that excellent streak on Wednesday.
They will expect to visit Argentina for the return leg next week with a lead to protect, with Newell's OB hoping to rediscover their form from the group stage in this competition.