Rodrigo Mora netted a first-half brace as River accounted for Argentine rivals Godoy Cruz 2-0 in the return leg in Buenos Aires. The two-goal win saw River progress 3-0 on aggregate.
Fresh after their weekend league fixture at Arsenal was rescheduled due to heavy rain, River made a bright start to proceedings.
In-form Uruguayan striker Mora opened the scoring in the 28th minute, lobbing the ball over onrushing goalkeeper Sebastian Moyano.
Mora was at it again four minutes later, firing the ball low into the bottom corner as he bagged his second consecutive brace to set up a showdown with Libertad.
Libertad beat Ecuadorian visitors Barcelona 2-0 in Wednesday's second leg.
Rodrigo Lopez and Jorge Gonzalez were both on target during the first half as the Paraguayan side successfully overturned a one-goal first-leg deficit.
Uruguayan forward Lopez broke the deadlock after eight minutes with a well-taken strike inside the area.
It got better for the home side one minute before half-time thanks to Gonzalez, who looped a header over Barcelona keeper Maximo Banguera.
Barcelona ended the match with nine men after Flavio Caicedo and Alex Bolanos saw red during the closing stages.
Meanwhile, two second-round first-leg fixtures began on Wednesday.
Andres Vilches scored twice as Chile's Huachipato beat Universidad Catolica 2-0.
Vilches got the ball rolling in the 13th minute before doubling the lead four minutes into the second half against their Ecuadorian opponents.
Club Universitario came from behind to earn a 2-2 draw at home to Peru outfit Cesar Vallejo in Bolivia.
Goals from Andy Pando and Daniel Chavez had Cesar Vallejo in a commanding position after 57 minutes.
But Universitario hit back through Ramiro Ballivian with 18 minutes remaining and Carlos Camacho completed the fightback in the fifth minute of injury time.