A disastrous day for Medellin's Jefferson Mena started in the 22nd minute as his own goal gave Atletico Nacional the lead.
Despite bossing the majority of the possession, Nacional struggled to get the second goal and kill off the game until a penalty was won on 68 minutes with Edwin Cardona converting.
After receiving a yellow card five minutes earlier, Mena was sent off for a second bookable offence on 72 minutes leaving Medellin reduced to ten men just before Nacional's Sherman Cardenas added another goal.
Medellin striker German Cano did pull a goal back on 77 minutes but a straight red to midfielder Javier Calle made the mission impossible for the visitors.
Santa Fe enjoyed the biggest win of the round after a 3-0 triumph at Itagui.
Goals to Wilder Medina and Luis Arias in the first half and a late strike from Yulian Anchico ensured a comfortable victory for Santa Fe.
Boyaca Chico survived a late rally from Deportivo Cali to run out 2-1 winners on the back of two first-half goals.
In other matches, newly-promoted Uniautonoma won 3-2 at home against Deportes Tolima, Millonarios overcame Envigado 2-1 and there was a 1-1 draw between La Equidad and Alianza Petrolera.
Once Caldas bolted to a 3-1 triumph against Fortelaza, Junior completed a thrilling 3-2 win at Atletico Huila and Deportivo Pasto cantered to a 3-1 result against Patriotas Boyaca.
