Elsewhere, Getafe still have work to do to make the last 16 and Celta Vigo prevailed in an all La Liga affair.
Real Madrid included the likes of Sergio Ramos, Angel Di Maria and Isco in their starting XI, but were unable to break down third tier opposition in the form of Olimpic Xativa as they were held 0-0 on the road.
Carlo Ancelotti's side will now be relying on the result of a second leg at Santiago Bernabeu to ensure that they avoid a major shock.
There were no such struggles for their cross-city rivals Atletico Madrid, as they eased past Sant Andreu 4-0.
The visitors were always in control on Catalan soil, with Raul Garcia firing them in front after just 13 minutes.
Arda Turan bagged a brace (20 & 56) to put them in complete control, before David Villa wrapped up the scoring six minutes from time.
Getafe were also in Catalunya on Saturday, and they required a 38th-minute leveller from Romania international Ciprian Marica to cancel out David Timor's 16th- minute opener and earn them a 1-1 draw.
One goal was all that Celta Vigo required to secure a first leg advantage over Athletic Bilbao, with Santi Mina getting them off to the perfect start with only seven minutes on the clock.
Segunda Liga Recreativo Huelva will hold a narrow advantage over Levante when they head to the home of the top flight outfit, with Hernandez Ruyman netting a dramatic stoppage-time winner to edge them in front.