Hernan Torres' men made it three one-goal wins in the group phase, edging Aguilas Pereira 2-1 on the back of a German Cano brace.
Medellin sit five points clear top of Group B, meaning a win in their return visit to Pereira - combined with a draw or worse for Deportivo Cali in their clash with Deportes Tolima - would send them through to the final with two games to spare.
Cali are the best chance of reeling in Medellin, after a 2-1 home win over 10-man Tolima.
The visitors to Cali took a 49th-minute lead through Yimmi Chara, despite going down to 10 men just prior to the interval when Juan Mahecha was dismissed.
But the home side fought back, Rafael Borre equalising seven minutes later before German Mera's late winner.
Santa Fe crucially denied Atletico Huila 3-3 in a thrilling encounter, to remain in pole position for a spot in the final.
Huila had the chance to go level with their opponents atop Group A with a victory, which they were on track for after scoring two goals in four minutes late in the second half to take the lead.
Juan Guaza's 77th-minute equaliser was followed by Carlos Diaz's goal, but Wilson Morelo saved face for Santa Fe five minutes later.
Huila remain three points back in second spot, while Atletico Nacional's 1-0 loss to Once Caldas left the two sides on three points.
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