Coming off a loss to LDU Quito in Group D, Penarol hammered San Jose 4-0 in Montevideo.
The Uruguayan host needed just two minutes to open the scoring, Lucas Viatri volleying in a cross from Giovanni Gonzalez.
Diego Lopez's Penarol would be in control by half-time as Cristian Lema headed in a Lucas Hernandez corner and Agustin Canobbio scored its third via a deflection.
Viatri produced a classy finish from 20 yards early in the second half as the hosts dominated, closing out their win despite Gaston Rodriguez missing a 76th-minute penalty.
In Group G, Athletico Paranaense responded to its opening defeat by thrashing Jorge Wilstermann 4-0.
The Brazilian side got fortunate with its opener just after the half-hour mark, Rony's strike deflecting off team-mate Marco Ruben and beating goalkeeper Arnaldo Gimenez.
Gimenez was at fault for the second goal, the shot-stopper unable to deal with a long-range effort from Tomas Andrade.
Renan Lodi and Bruno Guimaraes scored second-half goals for Athletico, sealing a comprehensive victory.
In the day's other game, Emelec and Huracan played out a 0-0 draw in Group B.