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| H | FK Žalgiris | - | Maccabi Haifa | 0:3 (0:1) | ||
| R | Maccabi Haifa | - | FK Žalgiris | 2:0 (1:0) | ||
| H: 28.09.2021 18:00 | R: 20.10.2021 16:00 | Sieger: Maccabi Haifa | ||||
| H | Rangers FC | - | Hammarby IF | 3:0 (1:0) | ||
| R | Hammarby IF | - | Rangers FC | 1:2 (0:0) | ||
| H: 28.09.2021 20:30 | R: 20.10.2021 19:00 | Sieger: Rangers FC | ||||
| H | BFC Daugavpils | - | FK Minsk | 0:4 (0:2) | ||
| R | FK Minsk | - | BFC Daugavpils | 2:0 (1:0) | ||
| H: 29.09.2021 13:00 | R: 20.10.2021 13:00 | Sieger: FK Minsk | ||||
| H | APOEL Nikosia | - | FK Kairat | 1:1 (1:1) | ||
| R | FK Kairat | - | APOEL Nikosia | 1:0 (1:0) | ||
| H: 29.09.2021 15:00 | R: 20.10.2021 13:00 | Sieger: FK Kairat | ||||
| H | Zvijezda 09 Bijeljina | - | Trabzonspor | 0:1 (0:1) | ||
| R | Trabzonspor | - | Zvijezda 09 Bijeljina | 2:0 (0:0) | ||
| H: 29.09.2021 15:00 | R: 20.10.2021 13:00 | Sieger: Trabzonspor | ||||
| H | Gabala FK | - | AZ Alkmaar | 0:4 (0:1) | ||
| R | AZ Alkmaar | - | Gabala FK | 7:0 (4:0) | ||
| H: 29.09.2021 15:00 | R: 19.10.2021 17:00 | Sieger: AZ Alkmaar | ||||
| H | MTK Budapest | - | AC Sparta Praha | 3:1 (2:1) | ||
| R | AC Sparta Praha | - | MTK Budapest | 3:3 (1:1) | ||
| H: 29.09.2021 16:00 | R: 20.10.2021 14:00 | Sieger: MTK Budapest | ||||
| H | Septemvri Sofia | - | Akademia e Futbollit | 3:0 (2:0) | ||
| R | Akademia e Futbollit | - | Septemvri Sofia | 1:1 (1:0) | ||
| H: 29.09.2021 16:00 | R: 19.10.2021 14:30 | Sieger: Septemvri Sofia | ||||
| H | FK Csikszereda | - | Angers SCO | 0:2 (0:1) | ||
| R | Angers SCO | - | FK Csikszereda | 3:0 (0:0) | ||
| H: 29.09.2021 17:00 | R: 20.10.2021 18:00 | Sieger: Angers SCO | ||||
| H | Pogoń Szczecin | - | Deportivo La Coruña | 3:0 (2:0) | ||
| R | Deportivo La Coruña | - | Pogoń Szczecin | 4:0 (3:0) | ||
| H: 29.09.2021 18:00 | R: 20.10.2021 20:00 | Sieger: Deportivo La Coruña | ||||
| H | PAOK Saloniki | - | MŠK Žilina | 1:5 (1:2) | ||
| R | MŠK Žilina | - | PAOK Saloniki | 2:0 (0:0) | ||
| H: 29.09.2021 18:00 | R: 20.10.2021 16:30 | Sieger: MŠK Žilina | ||||
| H | 1. FC Köln | - | KRC Genk | 2:4 (1:3) | ||
| R | KRC Genk | - | 1. FC Köln | 3:1 (1:1) | ||
| H: 29.09.2021 18:00 | R: 19.10.2021 18:00 | Sieger: KRC Genk | ||||
| H | NK Domžale | - | Empoli FC | 1:2 (1:1) | ||
| R | Empoli FC | - | NK Domžale | 1:1 (1:1) | ||
| H: 29.09.2021 19:00 | R: 20.10.2021 19:00 | Sieger: Empoli FC | ||||
| H | St Patrick's Athletic | - | Crvena Zvezda | 1:2 (0:2) | ||
| R | Crvena Zvezda | - | St Patrick's Athletic | 2:0 (1:0) | ||
| H: 29.09.2021 20:45 | R: 20.10.2021 17:00 | Sieger: Crvena Zvezda | ||||
| H | KF Shkëndija 79 | - | Hajduk Split | 0:2 (0:1) | ||
| R | Hajduk Split | - | KF Shkëndija 79 | 3:1 (2:1) | ||
| H: 30.09.2021 14:00 | R: 20.10.2021 17:00 | Sieger: Hajduk Split | ||||
| H | Rosenborg BK | - | FC Midtjylland | 2:4 (1:1) | ||
| R | FC Midtjylland | - | Rosenborg BK | 10:1 (3:1) | ||
| H: 30.09.2021 18:00 | R: 19.10.2021 15:30 | Sieger: FC Midtjylland | ||||
