Millonarios won their third title in the competition, after beating Junior in the double-legged final by a 2–1 aggregate score.

Atlético Nacional were the defending champions, having won the competition in the previous edition, but were knocked out by Junior in the quarter-finals.

Finally, in the round of 16, the eight third stage winners were joined by the four Copa Libertadores qualifiers (Deportes Tolima, Deportivo Cali, Millonarios, and Atlético Nacional) and the four Copa Sudamericana qualifiers (Junior, América de Cali, La Equidad, and Independiente Medellín), which entered the competition at this point.

[3] The schedule of the competition was as follows:[4] The first stage was played by 14 Categoría Primera B clubs, eight of which were seeded in the ties according to their placement in the 2021–II season aggregate table.

In case of a tie, extra time was not played and the winner was decided in a penalty shoot-out.