| Date | Home | Away | Result |
|---|---|---|---|
| 14/12/21 18:00 | Andorra CF | Celta Vigo | 1-2a.e.t |
| 14/12/21 18:00 | San Sebastian de los Reyes | CF Fuenlabrada | 4-5a.PSO |
| 14/12/21 19:00 | SD Huesca | FC Girona | 0-1 |
| 14/12/21 19:00 | CF Rayo Majadahonda | FC Malaga | 1-0 |
| 14/12/21 19:00 | Real Saragossa | Burgos CF | 2-0 |
| 14/12/21 20:00 | CD Alcoyano | UD Levante | 6-4a.PSO |
| 14/12/21 20:00 | Linares Deportivo | Deportivo Alaves | 2-1 |
| 14/12/21 20:00 | CF Cristo Atletico | Espanyol Barcelona | 1-2 |
| 15/12/21 18:00 | Bergantinos CF | Rayo Vallecano | 1-3 |
| 15/12/21 18:00 | Zamora CF | Real Sociedad | 0-3 |
| 15/12/21 18:00 | CE Andratx | FC Sevilla | 6-7a.PSO |
| 15/12/21 18:30 | Cultural y Deportiva Leonesa | CD Leganes | 2-3a.e.t |
| 15/12/21 19:00 | CD Castellon | FC Cartagena | 1-2 |
| 15/12/21 19:00 | Sporting Gijon | AD Alcorcon | 2-1a.e.t |
| 15/12/21 19:00 | SD Ponferradina | UD Ibiza Eivissa | 2-1a.e.t |
| 15/12/21 19:00 | Real Valladolid | UD Las Palmas | 3-1 |
| 15/12/21 20:00 | CD Teneriffa | SD Eibar | 1-2 |
| 15/12/21 20:00 | Unionistas de Salamanca | FC Elche | 0-1 |
| 15/12/21 20:00 | Atletico Sanluqueno CF | FC Villarreal | 1-7 |
| 16/12/21 18:00 | UD Llanera | RCD Mallorca | 0-6 |
| 16/12/21 18:00 | SD Amorebieta | UD Almeria | 1-2 |
| 16/12/21 18:00 | CF Talavera de la Reina | Real Betis Sevilla | 2-4a.e.t |
| 16/12/21 18:00 | CD Arenteiro | FC Valencia | 1-3a.e.t |
| 16/12/21 19:00 | CD Lugo | CD Mirandes | 1-2 |
| 16/12/21 20:00 | Albacete Balompie | FC Cadiz | 0-1 |
| 16/12/21 20:00 | Atletico Baleares | FC Getafe | 5-0 |
| 16/12/21 20:00 | Atletico Mancha Real | FC Granada | 1-0 |
| 16/12/21 20:00 | Deportivo La Coruna | CA Osasuna | 1-2 |