Barcelona were the defending champions, but they were eliminated by previous two seasons' runners-up Athletic Club in the round of 16.
Real Betis won the final 5–4 over Valencia on penalties following a 1–1 draw after extra time for their third Copa del Rey title.
In August 2021, the RFEF released the calendar of the competition and confirmed the format of the previous season would remain.
[4][5] Aldeano Hernani Nalón Solares Unami Victoria Injerto Mollerussa Penya Independent Utrillas Alicante Atarfe Industrial Atlético Espeleño Ceuta 6 de Junio Huracán Melilla Villa de Fortuna Jaraíz Laguna Mora San Agustín del Guadalix The first round was played by 112 of the 116 qualified teams, with the exceptions being the four participants of the 2022 Supercopa de España.
[6] Alavés Cádiz Celta Vigo Elche Espanyol Getafe Granada Levante Mallorca Osasuna Rayo Vallecano Real Betis Real Sociedad Sevilla Valencia Villarreal Alcorcón Almería Amorebieta Burgos Cartagena Eibar Fuenlabrada Girona Huesca Ibiza Las Palmas Leganés Lugo Málaga Mirandés Ponferradina Real Oviedo Sporting Gijón Tenerife Valladolid Zaragoza Albacete Alcoyano Algeciras Andorra Atlético Baleares Atlético Sanluqueño Badajoz Calahorra Castellón Cornellà Cultural Leonesa Deportivo La Coruña Extremadura Gimnàstic Internacional Linares Racing Ferrol Rayo Majadahonda Real Unión Sabadell San Fernando San Sebastián de los Reyes SD Logroñés Talavera Tudelano UCAM Murcia UD Logroñés Unionistas Zamora Águilas Alzira Andratx Arenteiro Atlético Mancha Real Atlético Pulpileño Bergantiños Brea Cacereño Calvo Sotelo Cayón Ceares Cristo Atlético Eldense Europa Gernika Gimnástica Segoviana Ibiza Islas Pitiusas Llanera Marchamalo Mensajero Montijo Náxara Panadería Pulido Peña Sport Racing Rioja San Juan San Roque de Lepe Teruel Unión Adarve Vélez Xerez Deportivo Córdoba Ebro Guijuelo Leioa Alicante Huracán Melilla Laguna Mollerussa San Agustín del Guadalix Solares Unami Utrillas Victoria Villa de Fortuna The draw was held on 3 December 2021 in the RFEF headquarters in Las Rozas.
Alavés Cádiz Celta Vigo Elche Espanyol Getafe Granada Levante Mallorca Osasuna Rayo Vallecano Real Betis Real Sociedad Sevilla Valencia Villarreal Alcorcón Almería Amorebieta Burgos Cartagena Eibar Fuenlabrada Girona Huesca Ibiza Las Palmas Leganés Lugo Málaga Mirandés Ponferradina Sporting Gijón Tenerife Valladolid Zaragoza Albacete Alcoyano Andorra Atlético Baleares Atlético Sanluqueño Castellón Cultural Leonesa Deportivo La Coruña Linares Rayo Majadahonda San Sebastián de los Reyes Talavera Unionistas Zamora Andratx Arenteiro Atlético Mancha Real Bergantiños Cristo Atlético Llanera The draw was held on 17 December 2021 in the RFEF headquarters in Las Rozas.
Athletic Bilbao Atlético Madrid Barcelona Real Madrid Cádiz Celta Vigo Elche Espanyol Mallorca Osasuna Rayo Vallecano Real Betis Real Sociedad Sevilla Valencia Villarreal Almería Cartagena Eibar Fuenlabrada Girona Leganés Mirandés Ponferradina Sporting Gijón Valladolid Zaragoza Alcoyano Atlético Baleares Linares Rayo Majadahonda Atlético Mancha Real The draw was held on 7 January 2022 in the RFEF headquarters in Las Rozas.