| 30/11/21 15:00 | CD Cayon | SD Huesca | 0-2 |
| 30/11/21 15:00 | CD Marchamalo | Real Valladolid | 0-1 |
| 30/11/21 17:30 | Naxara | Andorra CF | 0-1 |
| 30/11/21 18:00 | Victoria CF | FC Villarreal | 0-8 |
| 30/11/21 18:00 | Unami CP | Deportivo Alaves | 0-3 |
| 30/11/21 18:00 | Santos Laguna | FC Granada | 0-7 |
| 30/11/21 19:00 | UC Ceares | Sporting Gijon | 0-1 |
| 30/11/21 19:00 | Racing Rioja | FC Cartagena | 0-2 |
| 30/11/21 19:00 | CD Teruel | AD Alcorcon | 0-1 |
| 30/11/21 19:30 | Atletico Sanluqueno CF | CD Sabadell | 2-0 |
| 30/11/21 20:00 | CD Badajoz | CD Alcoyano | 0-3 |
| 30/11/21 20:00 | CD Ebro | Celta Vigo | 0-5 |
| 30/11/21 20:00 | Albacete Balompie | Racing de Ferrol | 2-1a.e.t |
| 30/11/21 20:00 | CFJ Mollerussa | FC Getafe | 1-5 |
| 30/11/21 20:00 | UD Montijo | Burgos CF | 0-1 |
| 30/11/21 20:00 | CDA Aguilas FC | UD Almeria | 4-6a.PSO |
| 01/12/21 15:30 | CD Mensajero | Real Saragossa | 0-1 |
| 01/12/21 17:30 | Bergantinos CF | CD Tudelano | 2-0 |
| 01/12/21 18:00 | SD Solares | Espanyol Barcelona | 2-3 |
| 01/12/21 18:00 | CF Algeciras | Unionistas de Salamanca | 1-2 |
| 01/12/21 18:00 | Cordoba CF | FC Sevilla | 0-1a.e.t |
| 01/12/21 18:00 | Gimnastica Segoviana | RCD Mallorca | 0-2a.e.t |
| 01/12/21 18:00 | CD Brea | UD Ibiza Eivissa | 0-2 |
| 01/12/21 19:00 | Alzira | CF Fuenlabrada | 0-1 |
| 01/12/21 19:00 | Atletico Mancha Real | Sadcf Internacional De Madrid Dsl | 2-1 |
| 01/12/21 19:00 | CE Andratx | Real Oviedo | 2-1 |
| 01/12/21 19:00 | AD San Juan | San Sebastian de los Reyes | 1-2 |
| 01/12/21 19:00 | UCAM Murcia | Deportivo La Coruna | 3-4a.e.t |
| 01/12/21 19:15 | CF Talavera de la Reina | UE Cornella | 2-0 |
| 01/12/21 19:30 | UD Extremadura | Zamora CF | 1-4 |
| 01/12/21 19:30 | Linares Deportivo | Gimnastica Segoviana | 6-5a.PSO |
| 01/12/21 19:30 | CD San Fernando | Cultural y Deportiva Leonesa | 2-3 |
| 01/12/21 19:30 | CE Europa | SD Amorebieta | 0-1 |
| 01/12/21 19:30 | CP Cacereno | SD Ponferradina | 1-2 |
| 01/12/21 19:30 | CD Arenteiro | SD Logrones | 2-1 |
| 01/12/21 19:30 | CD Calahorra | Atletico Baleares | 5-6a.PSO |
| 01/12/21 20:00 | Hercules Alicante | Real Betis Sevilla | 0-4 |
| 01/12/21 20:00 | Panaderia Pulido | Real Sociedad | 0-4 |
| 01/12/21 20:00 | CD San Roque de Lepe | CD Mirandes | 0-3 |
| 02/12/21 15:00 | Velez CF | UD Las Palmas | 2-3 |
| 02/12/21 18:00 | Huracan Melilla | UD Levante | 0-8 |
| 02/12/21 18:00 | CD Guijuelo | Rayo Vallecano | 4-5a.PSO |
| 02/12/21 18:00 | SD Gernika Club | SD Eibar | 1-2 |
| 02/12/21 18:00 | CF San Agustin | CA Osasuna | 0-4 |
| 02/12/21 18:30 | FC Pena Sport | FC Malaga | 0-3 |
| 02/12/21 18:30 | CD Utrillas | FC Valencia | 0-3 |
| 02/12/21 19:00 | CF Cristo Atletico | Real Union Club | 2-0 |
| 02/12/21 19:00 | CS Puertollano | FC Girona | 1-5 |
| 02/12/21 19:00 | UD Llanera | UD Logrones | 2-1 |
| 02/12/21 19:00 | CA Pulpileno | CD Castellon | 0-1 |
| 02/12/21 19:00 | SD Leioa | FC Elche | 0-2 |
| 02/12/21 19:15 | AD Union Adarve | CD Lugo | 5-6a.PSO |
| 02/12/21 19:30 | CD Eldense | CF Rayo Majadahonda | 0-1 |
| 02/12/21 19:45 | Deportivo Xerez | CD Leganes | 1-2 |
| 02/12/21 20:00 | CD Villa de Fortuna | FC Cadiz | 0-7 |
| 02/12/21 20:00 | CD Ibiza Islas Pitiusas | CD Teneriffa | 1-2a.e.t |
