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.
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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)
