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