Medellin led at half-time through German Cano but a three-minute blitz from Santa Fe just after the hour mark saw Santa Fe triumph, ahead of the second leg on Sunday.
Cristian Marrugo fed Cano in the 37th minute and the Argentine striker produced a sharp finish to give Medellin the lead in front of their home fans.
But it all unravelled for the hosts in the second half with Francisco Meza equalising for Santa Fe in the 65th minute, poking Armando Vargas' free-kick into the net.
Just three minutes later and the visitors were ahead with Wilson Morelo crunching the ball past Medellin goalkeeper Carlos Bejarano after Vargas released his team-mate with a fine long pass.
While Santa Fe had just 38 per cent possession, they impressed on the counter-attack with seven shots on target from just eight attempts.
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