Copa del Rey holders Barcelona will begin the defence of their title with a round-of-32 tie against Villanovense, while Real Madrid were paired with Cadiz in Friday's draw.
The draw for this round of the competition is seeded, with the seven teams representing Spain in the Champions League and Europa League guaranteed to face outfits from Segunda Division B leagues and Tercera Division.
Atletico Madrid - winners in 2013 - will face Reus, while last year's finalists Athletic Bilbao will take on Linense.
Elsewhere, Sevilla will play Logrones and Valencia come up against Barakaldo, while Villarreal take on Huesca.
The four all-La Liga ties drawn out of the hat were Real Betis against Sporting Gijon, Levante playing Espanyol, Las Palmas taking on Real Sociedad and Rayo Vallecano meeting Getafe.
Ties will be played over two legs on December 2 and December 16, with winners progressing to the last-16 stage, which is also seeded.
Draw in full:
Cadiz v Real Madrid
Villanovense v Barcelona
Barakaldo v Valencia
Reus v Atletico Madrid
Logrones v Sevilla
Linense v Athletic Bilbao
Huesca v Villarreal
Almeria v Celta Vigo
Leganes v Granada
Llagostera v Deportivo La Coruna
Mirandes v Malaga
Ponferradina v Eibar
Real Betis v Sporting Gijon
Levante v Espanyol
Las Palmas v Real Sociedad
Rayo Vallecano v Getafe
‘He instantly popped into our ratings as one of the best U21 midfielders in Europe. The impressive thing is Slot has made him into more of a no.6' Inside Ryan Gravenberch's transformation at Liverpool
‘I don’t think Liverpool would look at Ollie Watkins, a striker isn’t a pressing issue for them – it’s Arsenal who need one’ Former Reds star explains why his old club don’t need an out-and-out forward this summer
