Second-half goals from Jonathan Lacerda and Jose Abella made it back-to-back victories for the Liga MX side in Group 8.
Pedro Caixinha's men, sixth in their domestic league, are top of the group, five points clear of Deportivo Anzoategui, who have a game in hand.
After an even first half against Penarol, Lacerda gave the visitors the lead in the 54th minute at the Estadio Centenario in Montevideo.
Lacerda beat his marker to Carlos Quintero's cross from the right and tucked an easy first-time finish past goalkeeper Juan Castillo.
The visitors sealed the win in the first minute of additional time on the back of a fast counter-attack.
Andres Renteria found space down the left before delivering a well-weighted outside-of-the-boot pass to Abella, whose first touch was heavy but he still managed to finish.
Chilean outfit Union Espanola twice fought back from a goal down to earn a 2-2 draw at Independiente del Valle in Sangolqui.
Junior Sornoza put the Ecuadorian hosts ahead on 31 minutes, placing his penalty into the bottom corner after Jonathan Gonzalez had been brought down.
Cristian Chavez set up the equaliser in the 54th minute, releasing Sebastian Jaime down the right and the attacker smashed an effort across the goalkeeper and into the top corner.
Just four minutes later and the hosts regained the lead as Fernando Guerrero finished off after a scramble.
Chavez had an even quicker response for the visitors just a minute later, as the sides shared the spoils in their first game respectively in Group 2.
