The Uruguayan giants moved from third bottom to 12th with the emphatic victory, which was set up by a second-half double from Antonio Pacheco.
Penarol took the lead just before half-time at the Estadio Centenario in Montevideo through Luis Aguiar but the home side blew Miramar Misiones apart early in the second half as Jonathan Rodriguez struck in the 50th minute, followed by a brace from Pacheco in the 55th and 59th minutes.
Carlos Nunez completed the rout with 22 minutes remaining, leaving Miramar Misiones winless from nine games in the 2013-14 season.
At the top of the table, Penarol's arch-rivals Nacional saw their winning streak end at four games as Liverpool knocked off the league-leaders 2-1.
An own goal from Liverpool defender Andres Lamas gave Nacional the lead 11 minutes into the second half but the visitors fought back thanks to strikes from Martin Bonjour and Rodrigo Aguirre, with the latter coming in the 86th minute.
Liverpool then had Alejandro Pena and Gonzalo Freitas sent off after they took the lead but held on to claim a shock win.
The victory extended Liverpool's unbeaten run to five matches and they moved within five points of Nacional (21 points) on the table.
The second- and third-placed clubs in Uruguay's top tier, Danubio and River Plate were unable to take advantage of Nacional's defeat as they also lost their respective matches at home.
Danubio were stunned 1-0 by Wanderers, while Rentistas claimed three points at River Plate's Parque Federico Omar Saroldi.
In other results, Racing defeated Defensor Sporting 1-0, El Tanque Sisley were held to a 1-1 draw by Sud America, Fenix thumped Juventud de Las Piedras 4-2 and Cerro Largo overcame Cerro 2-1.
