The Colombian Primera A was split into two groups after the top eight teams qualified for the finals, with the winner of each group advancing to the decider.
And Santa Fe - who finished top at the end of the regular season - could not have asked for a better start after goals from Juan Roa, Wilson Morelo and Luis Arias inspired a narrow victory over 10-man Atletico Nacional at the Estadio El Campin in Group A.
Nacional, who won their opening game 1-0 win at home to Atletico Huila on Thursday, fell behind after five minutes.
Roa sprung the offside trap and fired the ball past Nacional goalkeeper Franco Armani, though the visitors hit back in the 32nd minute through Jonathan Copete, who headed home from close range.
Santa Fe were back in front six minutes later, when a mix up in Nacional's defence saw Morelo slot the ball underneath Armani.
The see-sawing first half took another twist on the half-time after Luis Paez equalised from the edge of the six-yard box.
But Santa Fe netted the eventual match-winner with 20 minutes remaining, Arias finding the bottom corner of the net.
Nacional ended the match with 10 men following Paez's dismissal for a second bookable offence 11 minutes from time.
In the other Group A match, 10-man Atletico Huila prevailed 2-1 against Once Caldas thanks to Juan Caicedo's first-half brace on Sunday.
Medellin - second during the regular season - were 3-2 winners over Deportivo Cali in their opening Group B fixture on Saturday.
Meanwhile, Aguilas Pereira rallied from two goals down to salvage a 2-2 draw at home to Deportes Tolima on Sunday.
