Defending Copa Libertadores champions River Plate will face Cruzeiro in the last 16, while last season's runners-up Boca Juniors are set to meet Athletico Paranaense again.
River's quest for back-to-back titles will continue against Brazilian giants Cruzeiro in a two-legged round-of-16 clash starting in July.
After edging Argentine rivals Boca in a dramatic final last season, River advanced to the knockout stage as runners-up to Internacional in Group A.
Meanwhile, two-time champions Cruzeiro – who last won the competition in 1997 having reached the final in 2009 – finished six points clear atop Group B.
Monday's draw in Paraguay also has two other mouth-watering ties pitting Argentina against South American rivals Brazil.
Six-time champions Boca will play Brazil's Paranaense – who won the Copa Sudamericana last year – after the two teams went head-to-head in Group G.
Boca finished two points clear of Paranaense, who won the first meeting 3-0 in Curitiba before the Argentine giants sealed top spot with a last-gasp 2-1 victory in Buenos Aires on matchday six.
The other Argentina-Brazil fixture will see Godoy Cruz take on Luiz Felipe Scolari's Palmeiras.
Copa Libertadores last-16 draw:
River Plate v Cruzeiro
Godoy Cruz v Palmeiras
Emelec v Flamengo
LDU Quito v Olimpia
Athletico Paranaense v Boca Juniors
Nacional v Internacional
Gremio v Libertad
San Lorenzo v Cerro Porteno