Penarol knocked out in Libertadores preliminary
Colombians Medellin went through 4-0 on aggregate after their emphatic win at home last week.
Penarol took the field at the Centenario stadium in Montevideo to a spectacular fireworks display but never looked like overturning the deficit, forcing only a couple of saves from Medellin goalkeeper Aldo Bobadilla.
Penarol, eliminated in the preliminary round in 2005 on their last Libertadores appearance, were once a major force in South American soccer but have suffered badly as European clubs buy up Uruguay's top players.
Ecuador's Deportivo Cuenca also progressed to the group stage with a 3-0 win over Deportivo Anzoategui of Venezuela.
Brazilian Rodrigo Teixeira scored twice before Ismael Villaba gave Cuenca a 3-2 aggregate win. The visitors had Edixon Cuevas and Luis Lobo sent off in the second half.