| 06 Nov 2021 | Real Oviedo SAD | 18:15 | UD Las Palmas SAD | Carlos Tartiere |
| 07 Nov 2021 | UD Almería SAD | 18:15 | Burgos CF SAD | Juegos del Mediterraneo |
| 07 Nov 2021 | Real Sociedad de Fútbol "B" | 21:00 | UD Ibiza SAD | Instalaciones de Zubieta |
| 07 Nov 2021 | FC Cartagena SAD | 18:15 | Málaga CF SAD | Estadio Municipal Cartagonova |
| 07 Nov 2021 | CD Tenerife SAD | 21:00 | Girona FC SAD | Heliodoro Rodríguez López |
| 06 Nov 2021 | CF Fuenlabrada SAD | 21:00 | SD Eibar SAD | Estadio Fernando Torres |
| 06 Nov 2021 | Real Valladolid CF SAD | 18:15 | CD Mirandés SAD | E.M. José Zorrilla |
| 05 Nov 2021 | SD Huesca SAD | 21:00 | CD Leganés SAD | Estadio El Alcoraz |
| 07 Nov 2021 | Real Zaragoza SAD | 16:00 | Real Sporting de Gijón SAD | La Romareda |
| 06 Nov 2021 | CD Lugo SAD | 16:00 | SD Ponferradina SAD | Ángel Carro |
| 07 Nov 2021 | AD Alcorcón SAD | 14:00 | SD Amorebieta | Santo Domingo |
