After kick-off at the Engenhao in Rio de Janeiro had been delayed for an hour due to a floodlighting failure, Fluminense took a fourth-minute lead through striker Rafael Moura.
A corner from the left was flicked on at the near post by midfielder Edinho and Moura headed home at the far post with goalkeeper Tobias Vargas clawing the ball out in vain.
Paraguayans Libertad equalised just past the hour when Ricardo Berna came out poorly to a long, high ball into the box and midfielder Rodolfo Gamarra headed over the stranded goalkeeper into the net.
Fluminense hit back with two brilliant goals in less than three minutes, midfielder Marquinhos with a low shot from outside the box in the 72nd and Argentine playmaker Dario Conca curling a free kick into the bottom corner.
Internacional's away goal at the Centenario in Montevideo gives the Brazilian team the upper hand against Penarol, who won the last of their five South American titles in 1987.
Winger Matias Corujo put the Uruguayan side ahead eight minutes before halftime when he curled a left-footed shot inside goalkeeper Renan's right-hand post from Argentine forward Alejandro Martinuccio's cross.
Midway through the second half, Brazil striker Leandro Damiao ran onto substitute Oscar's forward pass and edged between two defenders to hit a rising shot from 20 metres that dipped over goalkeeper Sebastian Sosa and in under the bar.
Penarol were lucky not to have Carlos Valdez sent off early in the match for bringing down Leandro Damiao in an Inter breakaway in which the defender looked like the last man. Suarez was booked.
"It's not such a bad result, we can play a good match there (in Brazil)," Corujo said of next week's second leg in Porto Alegre.
"They are great rivals, the last champions, but Penarol have to go out to play them as equals," he told Fox Sports.