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| U | Trabzonspor | - | FC Midtjylland | 2:5 (2:3) | ||
| R | FC Midtjylland | - | Trabzonspor | 5:0 (3:0) | ||
| U: 02.11.2021 12:00 | R: 23.11.2021 14:00 | Winnaars: FC Midtjylland | ||||
| U | Hajduk Split | - | FK Minsk | 3:0 (2:0) | ||
| R | FK Minsk | - | Hajduk Split | 1:1 (1:0) | ||
| U: 03.11.2021 16:00 | R: 24.11.2021 12:00 | Winnaars: Hajduk Split | ||||
| U | MTK Budapest | - | KRC Genk | 1:2 (1:0) | ||
| R | KRC Genk | - | MTK Budapest | 1:0 (0:0) | ||
| U: 03.11.2021 16:00 | R: 23.11.2021 18:00 | Winnaars: KRC Genk | ||||
| U | MŠK Žilina | - | FK Kairat | 3:2 (2:1) | ||
| R | FK Kairat | - | MŠK Žilina | 0:3 (1:0, 1:0) d.p. | ||
| U: 03.11.2021 16:30 | R: 24.11.2021 10:00 | Winnaars: MŠK Žilina | ||||
| U | Crvena Zvezda | - | Empoli FC | 1:1 (1:0) | ||
| R | Empoli FC | - | Crvena Zvezda | 5:0 (2:0) | ||
| U: 03.11.2021 16:30 | R: 23.11.2021 19:00 | Winnaars: Empoli FC | ||||
| U | Angers SCO | - | AZ Alkmaar | 0:1 (0:0) | ||
| R | AZ Alkmaar | - | Angers SCO | 5:4 (0:1, 0:1) d.p. | ||
| U: 03.11.2021 18:00 | R: 23.11.2021 16:00 | Winnaars: AZ Alkmaar | ||||
| U | Deportivo La Coruña | - | Maccabi Haifa | 5:1 (2:0) | ||
| R | Maccabi Haifa | - | Deportivo La Coruña | 3:0 (0:0) | ||
| U: 03.11.2021 20:00 | R: 08.12.2021 16:00 | Winnaars: Deportivo La Coruña | ||||
| U | Septemvri Sofia | - | Rangers FC | 2:4 (2:2) | ||
| R | Rangers FC | - | Septemvri Sofia | 3:0 (0:0) | ||
| U: 24.11.2021 14:00 | R: 07.12.2021 20:30 | Winnaars: Rangers FC | ||||
