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| 1st(1st leg) | Trabzonspor | - | FC Midtjylland | 2:5 (2:3) | ||
| 2nd (2nd leg) | FC Midtjylland | - | Trabzonspor | 5:0 (3:0) | ||
| 1st(1st leg): 02/11/2021 11:00 | 2nd (2nd leg): 23/11/2021 13:00 | Winner: FC Midtjylland | ||||
| 1st(1st leg) | Hajduk Split | - | FK Minsk | 3:0 (2:0) | ||
| 2nd (2nd leg) | FK Minsk | - | Hajduk Split | 1:1 (1:0) | ||
| 1st(1st leg): 03/11/2021 15:00 | 2nd (2nd leg): 24/11/2021 11:00 | Winner: Hajduk Split | ||||
| 1st(1st leg) | MTK Budapest | - | KRC Genk | 1:2 (1:0) | ||
| 2nd (2nd leg) | KRC Genk | - | MTK Budapest | 1:0 (0:0) | ||
| 1st(1st leg): 03/11/2021 15:00 | 2nd (2nd leg): 23/11/2021 17:00 | Winner: KRC Genk | ||||
| 1st(1st leg) | MŠK Žilina | - | FK Kairat | 3:2 (2:1) | ||
| 2nd (2nd leg) | FK Kairat | - | MŠK Žilina | 0:3 (1:0, 1:0) pso | ||
| 1st(1st leg): 03/11/2021 15:30 | 2nd (2nd leg): 24/11/2021 09:00 | Winner: MŠK Žilina | ||||
| 1st(1st leg) | Crvena Zvezda | - | Empoli FC | 1:1 (1:0) | ||
| 2nd (2nd leg) | Empoli FC | - | Crvena Zvezda | 5:0 (2:0) | ||
| 1st(1st leg): 03/11/2021 15:30 | 2nd (2nd leg): 23/11/2021 18:00 | Winner: Empoli FC | ||||
| 1st(1st leg) | Angers SCO | - | AZ Alkmaar | 0:1 (0:0) | ||
| 2nd (2nd leg) | AZ Alkmaar | - | Angers SCO | 5:4 (0:1, 0:1) pso | ||
| 1st(1st leg): 03/11/2021 17:00 | 2nd (2nd leg): 23/11/2021 15:00 | Winner: AZ Alkmaar | ||||
| 1st(1st leg) | Deportivo La Coruña | - | Maccabi Haifa | 5:1 (2:0) | ||
| 2nd (2nd leg) | Maccabi Haifa | - | Deportivo La Coruña | 3:0 (0:0) | ||
| 1st(1st leg): 03/11/2021 19:00 | 2nd (2nd leg): 08/12/2021 15:00 | Winner: Deportivo La Coruña | ||||
| 1st(1st leg) | Septemvri Sofia | - | Rangers FC | 2:4 (2:2) | ||
| 2nd (2nd leg) | Rangers FC | - | Septemvri Sofia | 3:0 (0:0) | ||
| 1st(1st leg): 24/11/2021 13:00 | 2nd (2nd leg): 07/12/2021 19:30 | Winner: Rangers FC | ||||
