Former Uruguay international striker Sebastian Abreu opened the scoring, while Franco Niell, Alejandro Donatti, Javier Correa and Hernan Encina completed the first-leg rout in the second half on Wednesday.
Argentine Primera Division outfit Rosario - who edged River Plate 5-4 to advance to the semi-finals - hit the front courtesy of Abreu's half-volley in the 14th minute as the Estadio San Juan Bicentenario.
Neill doubled the home side's lead eight minutes into the second half following a swift counter attack.
Donatti made it 3-0 from a corner nine minutes later, before Correa netted a goal of his own 10 minutes from time in San Juan.
The devastating display was capped in injury time by Encina, who looped the ball over the goalkeeper.
There was an upset in the other semi as Primera B side Huracan stunned Atletico Rafaela 2-0 away from home.
Huracan, who eliminated Boca Juniors, Banfield and Estudiantes en route to the semi-finals, were led by German Mandarino and Ramon Abila at the Estadio Antonio Romero.
Mandarino broke the deadlock in the 22nd minute after poking home a close-range rebound and Abila sealed the first-leg win with 19 minutes remaining.