United's U21s and Castilla will face off in the first round of the knockout stage, which has already begun after the group stage.
The match will be played in Manchester, will be a single-leg affair. The date is yet to be confirmed, pending agreement between the two clubs.
Castilla qualified for the quarterfinals as runners-up in Group A , behind Everton. They did so undefeated, with two wins (against Wolves and Everton) and two draws (against Southampton and Manchester City) , giving them eight points.
The quarterfinal tie will mark the debut of manager Julián López de Lerma in the competition, after Alvaro Arbeloa led the team in all four group stage matches, before taking charge of the senior tea.
Manchester United also reached the quarterfinals as runners-up in their group, only behind Borussia Dortmund.