Ivan Alonso scored a hat-trick for Rodolfo Arruabarrena's men, in what was a spiteful clash at Cerro's Estadio Municipal Arquitecto Antonio Eleuterio Ubilla.
Alonso opened his account for the match on the half-hour mark and doubled it 11 minutes later as the visitors to Melo led 2-0 at the break.
Enzo Borges got the home side on the board five minutes after the restart, but any hope of a comeback was swiftly ruled out seven minutes later when Alonso wrapped up his hat-trick to move to nine goals for the season - taking him second in the golden boot race.
Cerro Largo then went haywire as Guillermo Moretti and Alejandro Acosta were both dismissed in the final 26 minutes, while Nacional also lost a man - Juan Diaz - after he received two cautions.
Substitute Alexander Medina added Nacional's fourth goal in the dying stages, as they moved to 24 points - two behind league leaders Danubio, and one ahead of third-placed River Plate.
River Plate coughed up a two-goal lead late at home to Sud America, as they were kept to a 2-2 draw.
Sud America continued their unbeaten run in stunning fashion, going undefeated in four games after Angel Luna and Adrian Argacha both struck in the final three minutes to deny the hosts in Montevideo.
Earlier, Michael Santos and Alexander Rosso scored three minutes apart to fire River Plate to a comfortable lead just prior to the half-hour mark.
But they would not be able to make it consecutive victories, as they fell three points behind Danubio.
The league leaders dealt with a struggling Racing 2-0 at the Parque Osvaldo Roberto in the nation's capital, as Jonatan Alvez and Liber Quinones scored second-half goals.
El Tanque Sisley bounced back from their last-start home loss to Cerro with a 1-0 win on the road at Defensor Sporting.
Santiago Lamanna scored the winner for El Tanque Sisley, who kept a clean sheet against a Defensor side that put five goals past Nacional last time out.
Liverpool continued their unbeaten streak, making it seven games without defeat after fighting back twice to earn a 2-2 draw at home to Juventud de Las Piedras.
Facundo Barcelo converted from the spot both times for Liverpool - with the latter coming in the 84th minute to equalise for the second time.
Wanderers made it three straight victories with a 1-0 result over Rentistas - which took the winners to sixth on the table with 17 points.
Penarol picked up their second win in three outings with a 2-1 home success over Fenix, while Miramar Misiones broke their duck this season with a 2-1 road win over Cerro.
Miramar Misiones remain rooted to the foot of the table with seven points from 11 matches, with Juventud and Fenix (both eight) now in their sights.
‘After Manchester City’s recent form, maybe they’re the underdogs against Manchester United!’ Former Red Devils defender on this weekend’s derby
‘Arteta, Alonso, Emery, me… none of us were physical players – we needed the understanding of the game. That probably helped us move into management’: Premier League boss reveals reasons for natural career progression
