| 20 Apr 22 | r16  | América de CaliAmérica de Ca | 1 - 2 | Union MagdalenaUnion Magdale |
| 20 Apr 22 | r16 | Independiente MedellínIndependiente | 1 - 0 | Tigres FCTigres FC |
| 20 Apr 22 | r16 | La EquidadLa Equidad | 2 - 0 | Atlético BucaramangaAtlético Buca |
| 21 Apr 22 | r16 | Atlético JuniorAtlético Juni | 2 - 1 | Independiente Santa FeIndependiente |
| 21 Apr 22 | r16 | Deportes TolimaDeportes Toli | 3 - 2 | Deportivo PereiraDeportivo Per |
| 21 Apr 22 | r16 | Atlético NacionalAtlético Naci | 3 - 0 | Once CaldasOnce Caldas |
| 21 Apr 22 | r16 | Deportivo CaliDeportivo Cal | 1 - 3 | Fortaleza CEIFFortaleza CEI |
| 22 Apr 22 | r16 | Millonarios F.C.Millonarios F | 3 - 0 | Jaguares de CórdobaJaguares de C |
| 11 May 22 | r16 | Tigres FCTigres FC | 1 - 2 | Independiente MedellínIndependiente |
| 11 May 22 | r16 | Atlético BucaramangaAtlético Buca | 0 - 0 | La EquidadLa Equidad |
| 12 May 22 | r16 | Once CaldasOnce Caldas | 1 - 2 | Atlético NacionalAtlético Naci |
| 12 May 22 | r16 | Jaguares de CórdobaJaguares de C | 1 - 1 | Millonarios F.C.Millonarios F |
| 12 May 22 | r16 | Deportivo PereiraDeportivo Per | 1 - 1 | Deportes TolimaDeportes Toli |
| 12 May 22 | r16 | Independiente Santa FeIndependiente | 0 - 1 | Atlético JuniorAtlético Juni |
| 12 May 22 | r16 | Union MagdalenaUnion Magdale | 2 - 1 | América de CaliAmérica de Ca |
| 13 May 22 | r16 | Fortaleza CEIFFortaleza CEI | 1 - 1 | Deportivo CaliDeportivo Cal |
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