On 26 January, Istiklol announced that Manuchehr Safarov and Emomali Ahmadhon were on trial with the club, alongside various other Tajik and CIS players.

[1] On 27 January, Istiklol were drawn in to Group of A of the 2021 AFC Champions League, alongside Al Hilal, Shabab Al-Ahli and one of either, Beijing Sinobo Guoan, Brisbane Roar or Kaya–Iloilo.

[6] On 11 February, Istiklol announced the return of Nuriddin Davronov on loan from Borneo until after the AFC Champions League group stages in the summer of 2021.

[16] On the same day, Istiklol also announced the signings of Mukhriddin Khasanov from Khujand and Safarmad Gaforov, Manuchehr Safarov and Islom Zoirov from Lokomotiv-Pamir.

[27][28] On 22 August, Istiklol the signing of Petar Patev on a free transfer from Slavia Sofia, on a contract until the end of the season.

[29] On 7 November, Vahdat Hanonov and Manuchehr Safarov both left Istiklol to sign for Iranian club Persepolis, on contracts until 30 June 2024.