Nacional fell apart completely after Darwin Torres was sent off for a second bookable offence early in the second half and one goal from Jorge Rodriguez and two from Luis Aguiar completed the rout.
Penarol, whose last five-goal win in the fixture was in 1953, gave a fitting send-off to 38-year-old forward Antonio Pacheco, playing in the fixture for the last time.
Uruguayan media said that Pacheco has made 59 appearances in the fixture, a record for either team, and been on the winning side 30 times.
But it was a miserable afternoon for former Inter Milan and Uruguay midfielder Alvaro Recoba, also 38 and playing in the fixture for the last time for Nacional.
The win kept Penarol top of the Uruguay championship's second stage, one point clear of Wanderers who came from behind to beat eight-man Sud America 3-1.
Nicolas Royon put Sud America ahead in the 23rd minute but they had Emanuel Centurion given a straight red card shortly afterwards, while Maximiliano Pereiro and Adrian Argacha were dismissed for second bookable offences in the last 15 minutes.
(Reporting By Brian Homewood; editing by Amlan Chakraborty)
