| Tourney Name: | CAF Champions League knockout stage |
| Year: | 2021–22 |
| Matches: | 13 |
| Goals: | 28 |
| Prevseason: | 2020–21 |
| Nextseason: | 2022–23 |
The 2021–22 CAF Champions League knockout stage started on 15 April with the quarter-finals and ended on 30 May 2022 with the final to decide the champions of the 2021–22 CAF Champions League. A total of eight teams competed in the knockout stage.
Times are listed in local times.
The schedule was as follows.
| Round | Draw date | First leg | Second leg |
|---|---|---|---|
| Quarter-finals | 5 April 2022 | 15–16 April 2022 | 22–23 April 2022 |
| Semi-finals | 6–7 May 2022 | 13–14 May 2022 | |
| Final | 30 May 2022 | ||
Each tie in the knockout stage, apart from the final, was played over two legs, with each team playing one leg at home. The team that scored more goals on aggregate over the two legs advanced to the next round. If the aggregate score was level, the away goals rule was applied, i.e. the team that scored more goals away from home over the two legs advanced. If away goals were also equal, then extra time was not played and the winners were decided by a penalty shoot-out. In the final, which was played as a single match, if the score was level at the end of normal time, extra time was played and if the score was still level, the winners were decided by a penalty shoot-out.The mechanism of the draws for each round was as follows:
The knockout stage involves the 8 teams which qualify as winners and runners-up of each of the eight groups in the group stage.
| Group | width=200 | Winners | width=200 | Runners-up |
|---|---|---|---|---|
| A | Mamelodi Sundowns | Al Ahly | ||
| B | Raja Casablanca | ES Sétif | ||
| C | Espérance de Tunis | CR Belouizdad | ||
| D | Wydad AC | Petro de Luanda |
The bracket of the knockout stage was determined as follows:
| Round | Matchups | |
|---|---|---|
| Quarter-finals | (Group winners hosted second leg, matchups decided by draw, teams from same group cannot play each other)
| |
| Semi-finals | (Matchups and order of legs decided by draw, between winners QF1, QF2, QF3, QF4)
| |
| Final | Winners SF1 and SF2 faced each other to decide the champions |
The draw for the quarter-finals was held on 5 April 2022.
The first legs were played on 15 and 16 April, and the second legs were played on 22 and 23 April 2022.|}
Al Ahly won 3–2 on aggregate.----ES Sétif won 1–0 on aggregate.----Wydad AC won 1–0 on aggregate.----Petro de Luanda won 3–2 on aggregate.
The draw for the semi-finals was held on 5 April 2022 (after the quarter-finals draw).
The first legs were played on 7 May, and the second legs were played on 13 and 14 May 2022.|}
Al Ahly won 6–2 on aggregate.----Wydad AC won 4–2 on aggregate.
See main article: 2022 CAF Champions League Final. The final was played on 30 May 2022 at Stade Mohammed V, Casablanca.