The 2021 AFC Cup knockout stage was played from 25 August to 5 November 2021. A total of 8 teams competed in the knockout stage to decide the champions of the 2021 AFC Cup. Teams from ASEAN Zone did not compete in the knockout stage, due to the cancellation of group stage matches in ASEAN Zone.
The following teams advanced from the group stage:
<section begin=Format /> In the knockout stage, the eight teams played a single-elimination tournament. Each tie was played as a single match. Extra time and penalty shoot-out were used to decide the winners if necessary (Regulations Article 9.3 and 10.1).<section end=Format />
The schedule of each round is as follows (W: West Asia Zone; C: Central Asia Zone). Matches in the West Asia Zone will be played on Mondays and Tuesdays, while matches in the Central Zone and the Inter-zone play-offs will be played on Tuesdays and Wednesdays.
The bracket of the knockout stage was determined as follows:
<section begin=Bracket /> <section end=Bracket />
<section begin=Zonal semi-finals /> The West Asia Zonal semi-finals were played over one leg, with the home team determined by the draw mechanism based on which group runners-up qualify. A group winner hosted the match against a group runner-up. If two group winners played each other, one of the group winner (whose group runner-up qualify) hosted the match.
|+West Asia Zone
|+ASEAN Zone
<section end=Zonal semi-finals />
<section begin=Zonal finals /> The West Asia and Central Asia Zonal final were played over one leg, with the home team decided by draw. The winners of the West Asia Zonal final advanced to the final, while the winners of the Central Asia Zonal final advanced to the Inter-zone play-off semi-finals.
|+West Asia Zone
|+Central Asia Zone
|+ASEAN Zone
<section end=Zonal finals />
<section begin=Inter-zone play-off semi-finals /> After matches in ASEAN Zone was cancelled, there were only three teams which qualified to the Inter-zone play-off semi-finals, i.e., the winners of the South Asia Zone (Group D), the winners of the East Asia Zone (Group J), and the winners of the Central Zonal final. The three Zonal champions were drawn into two pairings where one club got a bye to the Inter-zone play-off final, which happened for Lee Man. The matchups and order of legs decided by draw, without any seeding with the winner of Central Zonal Final hosting the match and the winner of South Asia Zone being the away team.
<section end=Inter-zone play-off semi-finals />
<section begin=Inter-zone play-off final /> In the Inter-zone play-off final, the two teams which advanced from the Inter-zone play-off semi-finals played each other, with the order of legs determined by the Inter-zone play-off semi-final draw. The winners of the Inter-zone play-off final advanced to the final.
<section end=Inter-zone play-off final />
<section begin=Final /> The final was played over one leg, between the winners of the West Asia Zonal final and the winners of the Inter-zone play-off final. The home team was determined on a rotation basis, with the match hosted by the winners of the West Asia Zonal final, as in the case of odd-numbered years (Regulations 9.1.2). <section end=Final />