| Tourney Name: | CAF Confederation Cup knockout stage |
| Year: | 2021–22 |
| Matches: | 13 |
| Goals: | 20 |
| Prevseason: | 2020–21 |
| Nextseason: | 2022–23 |
The 2021–22 CAF Confederation Cup knockout stage started on 17 April with the quarter-finals and ended on 20 May 2022 with the final to decide the champions of the 2021–22 CAF Confederation Cup. 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 | 17 April 2022 | 24 April 2022 |
| Semi-finals | 8 May 2022 | 15 May 2022 | |
| Final | 20 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 involved 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 | Al Ahli Tripoli | Pyramids | ||
| B | Orlando Pirates | Al Ittihad | ||
| C | TP Mazembe | Al Masry | ||
| D | RS Berkane | Simba |
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 17 April, and the second were played on 24 April 2022.|}
1–1 on aggregate. Orlando Pirates won 4–3 on penalties.----Al Ahli Tripoli won 1–0 on aggregate.----TP Mazembe won 2–0 on aggregate.----2–2 on aggregate. RS Berkane won on away goals.
The draw for the semi-finals was held on 5 April 2022 (after the quarter-finals draw).
The first legs were played on 8 May, and the second legs were played on 15 May 2022.|}
Orlando Pirates won 2–1 on aggregate.----RS Berkane won 4–2 on aggregate.
See main article: 2022 CAF Confederation Cup Final. The final was played on 20 May 2022 at Godswill Akpabio International Stadium, Uyo.