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| 1st(1st leg) | Shakter Karaganda | - | Maccabi Tel Aviv | 1:2 (0:0) | ||
| 2nd (2nd leg) | Maccabi Tel Aviv | - | Shakter Karaganda | 2:0 (2:0) | ||
| 1st(1st leg): 19/08/2021 14:00 | 2nd (2nd leg): 26/08/2021 18:30 | Winner: Maccabi Tel Aviv | ||||
| 1st(1st leg) | FC Flora | - | Shamrock Rovers | 4:2 (2:1) | ||
| 2nd (2nd leg) | Shamrock Rovers | - | FC Flora | 0:1 (0:0) | ||
| 1st(1st leg): 19/08/2021 17:00 | 2nd (2nd leg): 26/08/2021 19:45 | Winner: FC Flora | ||||
| 1st(1st leg) | Qarabağ FK | - | Aberdeen FC | 1:0 (1:0) | ||
| 2nd (2nd leg) | Aberdeen FC | - | Qarabağ FK | 1:3 (0:2) | ||
| 1st(1st leg): 19/08/2021 17:00 | 2nd (2nd leg): 26/08/2021 19:45 | Winner: Qarabağ FK | ||||
| 1st(1st leg) | Kuopion PS | - | 1. FC Union Berlin | 0:4 (0:3) | ||
| 2nd (2nd leg) | 1. FC Union Berlin | - | Kuopion PS | 0:0 (0:0) | ||
| 1st(1st leg): 19/08/2021 17:00 | 2nd (2nd leg): 26/08/2021 19:15 | Winner: 1. FC Union Berlin | ||||
| 1st(1st leg) | Raków Częstochowa | - | KAA Gent | 1:0 (0:0) | ||
| 2nd (2nd leg) | KAA Gent | - | Raków Częstochowa | 3:0 (1:0) | ||
| 1st(1st leg): 19/08/2021 17:00 | 2nd (2nd leg): 26/08/2021 19:00 | Winner: KAA Gent | ||||
| 1st(1st leg) | FK Žalgiris | - | FK Bodø/Glimt | 2:2 (1:0) | ||
| 2nd (2nd leg) | FK Bodø/Glimt | - | FK Žalgiris | 1:0 (0:0) | ||
| 1st(1st leg): 19/08/2021 18:00 | 2nd (2nd leg): 26/08/2021 17:00 | Winner: FK Bodø/Glimt | ||||
| 1st(1st leg) | Neftçi PFK | - | Maccabi Haifa | 3:3 (0:1) | ||
| 2nd (2nd leg) | Maccabi Haifa | - | Neftçi PFK | 4:0 (2:0) | ||
| 1st(1st leg): 19/08/2021 18:00 | 2nd (2nd leg): 26/08/2021 18:00 | Winner: Maccabi Haifa | ||||
| 1st(1st leg) | Riga FC | - | Lincoln Red Imps | 1:1 (0:0) | ||
| 2nd (2nd leg) | Lincoln Red Imps | - | Riga FC | 3:1 (1:1, 1:1) aet | ||
| 1st(1st leg): 19/08/2021 18:00 | 2nd (2nd leg): 26/08/2021 17:00 | Winner: Lincoln Red Imps | ||||
| 1st(1st leg) | Viktoria Plzeň | - | CSKA Sofia | 2:0 (1:0) | ||
| 2nd (2nd leg) | CSKA Sofia | - | Viktoria Plzeň | 3:0 (1:0, 2:0) aet | ||
| 1st(1st leg): 19/08/2021 18:00 | 2nd (2nd leg): 26/08/2021 18:00 | Winner: CSKA Sofia | ||||
| 1st(1st leg) | LASK | - | St. Johnstone FC | 1:1 (0:1) | ||
| 2nd (2nd leg) | St. Johnstone FC | - | LASK | 0:2 (0:0) | ||
| 1st(1st leg): 19/08/2021 18:00 | 2nd (2nd leg): 26/08/2021 19:00 | Winner: LASK | ||||
| 1st(1st leg) | Hapoel Be'er Sheva | - | Anorthosis Famagusta | 0:0 (0:0) | ||
| 2nd (2nd leg) | Anorthosis Famagusta | - | Hapoel Be'er Sheva | 3:1 (1:1) | ||
| 1st(1st leg): 19/08/2021 18:00 | 2nd (2nd leg): 26/08/2021 18:00 | Winner: Anorthosis Famagusta | ||||
| 1st(1st leg) | CS FOLA Esch | - | FK Kairat | 1:4 (1:3) | ||
| 2nd (2nd leg) | FK Kairat | - | CS FOLA Esch | 3:1 (3:1) | ||
| 1st(1st leg): 19/08/2021 18:30 | 2nd (2nd leg): 26/08/2021 15:00 | Winner: FK Kairat | ||||
| 1st(1st leg) | FC Basel | - | Hammarby IF | 3:1 (1:0) | ||
| 2nd (2nd leg) | Hammarby IF | - | FC Basel | 3:4 (0:0, 2:0, 3:1) pso | ||
| 1st(1st leg): 19/08/2021 18:30 | 2nd (2nd leg): 26/08/2021 18:00 | Winner: FC Basel | ||||
| 1st(1st leg) | Trabzonspor | - | AS Roma | 1:2 (0:0) | ||
| 2nd (2nd leg) | AS Roma | - | Trabzonspor | 3:0 (1:0) | ||
| 1st(1st leg): 19/08/2021 18:30 | 2nd (2nd leg): 26/08/2021 18:00 | Winner: AS Roma | ||||
| 1st(1st leg) | Stade Rennais | - | Rosenborg BK | 2:0 (1:0) | ||
| 2nd (2nd leg) | Rosenborg BK | - | Stade Rennais | 1:3 (0:2) | ||
| 1st(1st leg): 19/08/2021 19:00 | 2nd (2nd leg): 26/08/2021 18:00 | Winner: Stade Rennais | ||||
| 1st(1st leg) | RSC Anderlecht | - | Vitesse | 3:3 (2:1) | ||
| 2nd (2nd leg) | Vitesse | - | RSC Anderlecht | 2:1 (1:0) | ||
| 1st(1st leg): 19/08/2021 19:00 | 2nd (2nd leg): 26/08/2021 18:00 | Winner: Vitesse | ||||
| 1st(1st leg) | PAOK Saloniki | - | HNK Rijeka | 1:1 (0:1) | ||
| 2nd (2nd leg) | HNK Rijeka | - | PAOK Saloniki | 0:2 (0:1) | ||
| 1st(1st leg): 19/08/2021 19:00 | 2nd (2nd leg): 26/08/2021 19:00 | Winner: PAOK Saloniki | ||||
| 1st(1st leg) | Feyenoord | - | IF Elfsborg | 5:0 (3:0) | ||
| 2nd (2nd leg) | IF Elfsborg | - | Feyenoord | 3:1 (1:0) | ||
| 1st(1st leg): 19/08/2021 19:00 | 2nd (2nd leg): 26/08/2021 18:00 | Winner: Feyenoord | ||||
| 1st(1st leg) | Sivasspor | - | FC København | 1:2 (0:0) | ||
| 2nd (2nd leg) | FC København | - | Sivasspor | 5:0 (2:0) | ||
| 1st(1st leg): 19/08/2021 19:00 | 2nd (2nd leg): 26/08/2021 18:00 | Winner: FC København | ||||
| 1st(1st leg) | FK Jablonec | - | MŠK Žilina | 5:1 (4:0) | ||
| 2nd (2nd leg) | MŠK Žilina | - | FK Jablonec | 0:3 (0:1) | ||
| 1st(1st leg): 19/08/2021 19:00 | 2nd (2nd leg): 26/08/2021 17:00 | Winner: FK Jablonec | ||||
| 1st(1st leg) | Paços de Ferreira | - | Tottenham Hotspur | 1:0 (1:0) | ||
| 2nd (2nd leg) | Tottenham Hotspur | - | Paços de Ferreira | 3:0 (2:0) | ||
| 1st(1st leg): 19/08/2021 19:30 | 2nd (2nd leg): 26/08/2021 19:45 | Winner: Tottenham Hotspur | ||||
| 1st(1st leg) | CD Santa Clara | - | Partizan | 2:1 (1:0) | ||
| 2nd (2nd leg) | Partizan | - | CD Santa Clara | 2:0 (2:0) | ||
| 1st(1st leg): 19/08/2021 21:30 | 2nd (2nd leg): 26/08/2021 20:00 | Winner: Partizan | ||||
