Defending champion Barcelona and Real Madrid will start their Copa del Rey campaigns against third-tier clubs.
Barcelona will travel to western Spain to play the first leg against Villanovense on Oct. 28 to make room in the calendar to play at the Club World Cup.
Real Madrid, which will face Cadiz, and the rest of the teams will play their first legs during the first week of December.
Atletico Madrid, Valencia and Sevilla were also paired with third-tier teams.
This round is the first to include the 20 first-division teams.
It will include four direct matchups between topflight clubs: Real Betis vs. Sporting Gijon; Levante vs. Espanyol; Las Palmas vs. Real Sociedad; and Rayo Vallecano vs. Getafe.