Juan Osorio's men finished the six-match group phase unbeaten, and brought up their fifth win - and fourth in succession - with the home result.
Jhon Valoy put Nacional ahead just prior to half-time, before Rodin Quinones made things more comfortable with a second goal with 10 minutes to play.
Luis Arias' 89th-minute penalty for Santa Fe made for a nervous finish, but Nacional held on to move into the finals in fine form.
Junior finished second to the group winners after dispatching of Itagui 4-1 to move to 10 points.
Luis Ruiz scored all four goals for Junior, who snapped a two-match losing streak.
In a game of many twists and turns, Yessi Mena opened the scoring in the fourth minute as Itagui threatened a boil over.
Ruiz wrapped up his hat-trick in the 23rd minute, taking just 12 minutes to go from zero goals to three in a blistering display for the home side.
However, Itagui's hopes of a comeback were boosted by a red card to Junior's Michael Ortega just prior to the break.
But they blew their chances with the man advantage when John Restrepo was dismissed for the visitors, and coincidentally Itagui finished with fewer men when Javier Lopez was also sent off.
Ruiz scored his fourth in the 90th minute, capping a brilliant individual display.
Finalists Deportivo Cali's perfect Group B campaign was blotched, as they fell to Deportivo Pasto 3-2 on the road.
Cali led on five minutes courtesy of a Victor Giraldo penalty, but Pasto immediately took the ascendancy - with three goals in 18 minutes putting the group leaders to the sword.
A late goal back from Steven Mendoza from the spot gave Pasto some nervous moments, as the hosts were also down to 10 after Eder Ruales was sent off on 79 minutes.
Once Caldas dropped to third in the group, level with bottom-placed Millonarios on six points, after the latter beat the former 3-1.
Caldas led on 27 minutes at Millonarios, but a sterling late show from the home side saw them to a two-goal victory.
A Dayro Moreno brace in six minutes quickly turned the tide, before Jonathan Agudelo sealed the three points for Millonarios - who snapped a three-match losing run.
