Friday's (AEST) 1-1 draw away to Paraguayan side Cerro Porteno was enough for River to reach the semi-finals 3-1 on aggregate.
River – seeking back-to-back titles – carried a 2-0 lead into the second leg thanks to goals from Ignacio Fernandez and Rafael Borre in Buenos Aires.
Cerro Porteno sparked hope of a comeback in the eighth minute when former Borussia Dortmund forward Nelson Valdez put the home side ahead on the night.
Valdez – a 77-time Paraguay international – glanced a header past River goalkeeper Franco Armani.
But Cerro Porteno's hopes were dashed when River midfielder Nicolas De La Cruz scored seven minutes into the second half with a ferocious volley.
River will now go head-to-head with Boca in a blockbuster all-Argentinian Libertadores semi-final.
It comes after River claimed the 2018 trophy with a 5-3 aggregate win over Boca in their controversial two-legged showdown.
The second leg had to be rearranged and moved to Real Madrid's Santiago Bernabeu in December after the match was twice suspended in November due to an attack on Boca's team bus by supporters.