On 25 February, Jorge Sampaoli stepped down as Atlético's manager and on the following day the club named assistant coach Lucas Gonçalves to the position on an interim basis.

[6] On 25 May, they beat Deportivo La Guaira 4–0 at the Mineirão, concluding their Copa Libertadores group stage run with the best overall campaign, with five wins and one draw.

This was the first time a Brazilian team was able to beat Boca Juniors in the penalty shootouts of a Libertadores match, after five consecutive wins by the Argentines in previous encounters.

[15] This marked only the second time a team knocked out both River Plate and Boca Juniors in the same edition of the competition, following Independiente del Valle in 2016.

[17] On 28 September, the team was knocked out in the semi-finals of the Copa Libertadores by Palmeiras on the away goal rule, after 0–0 away draw in the first leg and a 1–1 score at home in the second.

[21] Atlético finished the month of November with six wins and a draw in the league, with ten points ahead of second placed Flamengo.

[22] On 2 December, Atlético were crowned the 2021 Campeonato Brasileiro Série A champions in a thrilling contest away against Bahia: after going 2–0 down at the start of the second half, the team responded scoring three goals in an interval of five minutes, first with Hulk from a penalty kick and then with a brace from Keno.