A first-half brace from Andre led the way for Gremio, who set up an all-Brazilian quarter-final against Palmeiras on Thursday.
Goals from Diego Tardelli and David Braz helped Gremio beat Libertad in the Copa Libertadores.
The draw for the Copa Libertadores round of 16 took place in Paraguay on Monday.
Wednesday's results left all three teams on 10 points but Flamengo (+6) and LDU Quito (+4) pipped Penarol (+2) on goal difference.
Cruzeiro made it five wins from five games in Group B as Atletico Mineiro failed to progress.
After three consecutive draws, River Plate defeated lowly Peruvian side Alianza Lima 3-0 on Thursday to move up to second in the group.
Boca Juniors scored four goals against Jorge Wilstermann on Wednesday, after Cruzeiro's Fred celebrated a first-half hat-trick.
Gremio only have one point from three Group H fixtures following Thursday's 1-0 loss away to Universidad Catolica.
Boca Juniors and Palmeiras both won 3-0 in the Copa Libertadores on Tuesday.
Last season's runners-up Boca Juniors were held by Bolivian hosts Jorge Wilstermann in Group G on Tuesday.