The tournament began on 15 June 2021 during the mid-season break due to the 2021 Copa América and ended on 4 September 2021, with the final match on neutral ground.
[1][2] Colo-Colo were able to defend the title won in the previous edition of the competition, winning their thirteenth Copa Chile after beating Everton in the final by a 2–0 score.
Similar to the previous edition, ties in this round were single-legged, with the team from the lower tier hosting the match.
The team with the highest seed assigned in the draw hosted the second leg.
On 19 August 2021, ANFP confirmed that the 2021 Copa Chile final would be played on 4 September 2021 in Talca.