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| U | Shakter Karaganda | - | Maccabi Tel Aviv | 1:2 (0:0) | ||
| R | Maccabi Tel Aviv | - | Shakter Karaganda | 2:0 (2:0) | ||
| U: 19.08.2021 15:00 | R: 26.08.2021 19:30 | Winnaars: Maccabi Tel Aviv | ||||
| U | FC Flora | - | Shamrock Rovers | 4:2 (2:1) | ||
| R | Shamrock Rovers | - | FC Flora | 0:1 (0:0) | ||
| U: 19.08.2021 18:00 | R: 26.08.2021 20:45 | Winnaars: FC Flora | ||||
| U | Qarabağ FK | - | Aberdeen FC | 1:0 (1:0) | ||
| R | Aberdeen FC | - | Qarabağ FK | 1:3 (0:2) | ||
| U: 19.08.2021 18:00 | R: 26.08.2021 20:45 | Winnaars: Qarabağ FK | ||||
| U | Kuopion PS | - | 1. FC Union Berlin | 0:4 (0:3) | ||
| R | 1. FC Union Berlin | - | Kuopion PS | 0:0 (0:0) | ||
| U: 19.08.2021 18:00 | R: 26.08.2021 20:15 | Winnaars: 1. FC Union Berlin | ||||
| U | Raków Częstochowa | - | KAA Gent | 1:0 (0:0) | ||
| R | KAA Gent | - | Raków Częstochowa | 3:0 (1:0) | ||
| U: 19.08.2021 18:00 | R: 26.08.2021 20:00 | Winnaars: KAA Gent | ||||
| U | FK Žalgiris | - | FK Bodø/Glimt | 2:2 (1:0) | ||
| R | FK Bodø/Glimt | - | FK Žalgiris | 1:0 (0:0) | ||
| U: 19.08.2021 19:00 | R: 26.08.2021 18:00 | Winnaars: FK Bodø/Glimt | ||||
| U | Neftçi PFK | - | Maccabi Haifa | 3:3 (0:1) | ||
| R | Maccabi Haifa | - | Neftçi PFK | 4:0 (2:0) | ||
| U: 19.08.2021 19:00 | R: 26.08.2021 19:00 | Winnaars: Maccabi Haifa | ||||
| U | Riga FC | - | Lincoln Red Imps | 1:1 (0:0) | ||
| R | Lincoln Red Imps | - | Riga FC | 3:1 (1:1, 1:1) n.v. | ||
| U: 19.08.2021 19:00 | R: 26.08.2021 18:00 | Winnaars: Lincoln Red Imps | ||||
| U | Viktoria Plzeň | - | CSKA Sofia | 2:0 (1:0) | ||
| R | CSKA Sofia | - | Viktoria Plzeň | 3:0 (1:0, 2:0) n.v. | ||
| U: 19.08.2021 19:00 | R: 26.08.2021 19:00 | Winnaars: CSKA Sofia | ||||
| U | LASK | - | St. Johnstone FC | 1:1 (0:1) | ||
| R | St. Johnstone FC | - | LASK | 0:2 (0:0) | ||
| U: 19.08.2021 19:00 | R: 26.08.2021 20:00 | Winnaars: LASK | ||||
| U | Hapoel Be'er Sheva | - | Anorthosis Famagusta | 0:0 (0:0) | ||
| R | Anorthosis Famagusta | - | Hapoel Be'er Sheva | 3:1 (1:1) | ||
| U: 19.08.2021 19:00 | R: 26.08.2021 19:00 | Winnaars: Anorthosis Famagusta | ||||
| U | CS FOLA Esch | - | FK Kairat | 1:4 (1:3) | ||
| R | FK Kairat | - | CS FOLA Esch | 3:1 (3:1) | ||
| U: 19.08.2021 19:30 | R: 26.08.2021 16:00 | Winnaars: FK Kairat | ||||
| U | FC Basel 1893 | - | Hammarby IF | 3:1 (1:0) | ||
| R | Hammarby IF | - | FC Basel 1893 | 3:4 (0:0, 2:0, 3:1) d.p. | ||
| U: 19.08.2021 19:30 | R: 26.08.2021 19:00 | Winnaars: FC Basel 1893 | ||||
| U | Trabzonspor | - | AS Roma | 1:2 (0:0) | ||
| R | AS Roma | - | Trabzonspor | 3:0 (1:0) | ||
| U: 19.08.2021 19:30 | R: 26.08.2021 19:00 | Winnaars: AS Roma | ||||
| U | Stade Rennais | - | Rosenborg BK | 2:0 (1:0) | ||
| R | Rosenborg BK | - | Stade Rennais | 1:3 (0:2) | ||
| U: 19.08.2021 20:00 | R: 26.08.2021 19:00 | Winnaars: Stade Rennais | ||||
| U | RSC Anderlecht | - | Vitesse | 3:3 (2:1) | ||
| R | Vitesse | - | RSC Anderlecht | 2:1 (1:0) | ||
| U: 19.08.2021 20:00 | R: 26.08.2021 19:00 | Winnaars: Vitesse | ||||
| U | PAOK Saloniki | - | HNK Rijeka | 1:1 (0:1) | ||
| R | HNK Rijeka | - | PAOK Saloniki | 0:2 (0:1) | ||
| U: 19.08.2021 20:00 | R: 26.08.2021 20:00 | Winnaars: PAOK Saloniki | ||||
| U | Feyenoord | - | IF Elfsborg | 5:0 (3:0) | ||
| R | IF Elfsborg | - | Feyenoord | 3:1 (1:0) | ||
| U: 19.08.2021 20:00 | R: 26.08.2021 19:00 | Winnaars: Feyenoord | ||||
| U | Sivasspor | - | FC Kopenhagen | 1:2 (0:0) | ||
| R | FC Kopenhagen | - | Sivasspor | 5:0 (2:0) | ||
| U: 19.08.2021 20:00 | R: 26.08.2021 19:00 | Winnaars: FC Kopenhagen | ||||
| U | FK Jablonec | - | MŠK Žilina | 5:1 (4:0) | ||
| R | MŠK Žilina | - | FK Jablonec | 0:3 (0:1) | ||
| U: 19.08.2021 20:00 | R: 26.08.2021 18:00 | Winnaars: FK Jablonec | ||||
| U | Paços de Ferreira | - | Tottenham Hotspur | 1:0 (1:0) | ||
| R | Tottenham Hotspur | - | Paços de Ferreira | 3:0 (2:0) | ||
| U: 19.08.2021 20:30 | R: 26.08.2021 20:45 | Winnaars: Tottenham Hotspur | ||||
| U | CD Santa Clara | - | Partizan | 2:1 (1:0) | ||
| R | Partizan | - | CD Santa Clara | 2:0 (2:0) | ||
| U: 19.08.2021 22:30 | R: 26.08.2021 21:00 | Winnaars: Partizan | ||||
