Nestor Silvera scored the first goal at the Libertadores de America stadium, named after Independiente's record seven South American club titles and erected in the same place as the old ground built in 1928, before Ignacio Piatti added two more.
Silvera put Argentina's Red Devils ahead in the 12th minute from Piatti's lay-off, but Federico Nieto equalised in the 35th for his seventh goal of the season.
Midfielder Piatti gave Independiente a halftime lead when he ran through the defence to score in the 43rd and scored again in the 72nd in another breakaway, weaving past keeper Diego Pozo and defender Ariel Garce before shooting into the open net.
By the time of Independiente's third, Colon striker and captain Esteban Fuertes had been sent off for elbowing. Midfielder Alfredo Ramirez pulled another goal back in the 89th minute.
While a near full house of 50,000 were celebrating at Independiente, their arch-rivals Racing Club, whose ground is a few hundred metres across a stretch of wasteland in the suburb of Avellaneda, were seething after German Lothar Matthaus opted at the last minute not to take over as their coach.
RELEGATION LOOMING
Racing, whose 1-0 loss away to Newell's Old Boys on Tuesday left them joint bottom with five points, no wins and in serious danger of relegation, were looking closer to home for a new coach, approaching Uruguayan Sergio Markarian.
Three teams hold the joint lead with 23 points from 11 matches with South American champions Estudiantes top on goal difference after their 2-1 away win over Godoy Cruz on Tuesday.
Banfield, who won 1-0 at Gimnasia-La Plata on Wednesday with a 10th goal for Uruguayan striker Santiago Silva, the championship's top scorer, are second.
"We're still dreaming. We won at a very tough ground...Now we face a very difficult rival in what I think will be the most important match of the next round," said Silva referring to Banfield's home game with Estudiantes at the weekend.
Newell's are third, also on 23 points, while Diego Simeone's San Lorenzo are fourth with 22 points after twice coming from behind to beat Arsenal 3-2.
Colon and title holders Velez Sarsfield, who won 2-1 at Atletico Tucuman on Tuesday, have 21 points and Independiente 20.
‘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
