Sevilla booked their spot in the round of 16 with a 5-1 win over Sabadell, while Atletico Madrid and Barcelona both won big on Wednesday.
Loanee Iago Aspas scored a sensational hat-trick in the space of four minutes at the Estadio Ramon Sanchez Pizjuan as Sevilla crushed second-tier outfit Sabadell 11-2 on aggregate.
Sabadell took a surprise 22nd-minute lead courtesy of Juan Collantes' penalty after Sevilla defender Timothee Kolodziejczak fouled the Spanish midfielder.
But Sevilla were back on level terms 13 minutes later when Kevin Gameiro controlled the ball just outside the six-yard box and fired beyond visiting goalkeeper Nauzet Perez.
Aspas - on loan from Liverpool - took centre stage after the break as he netted three quick-fire goals.
The Liverpool outcast scored his first in the 58th minute, before he looped the ball over Nauzet with the outside of his boot just 60 seconds later.
Aspas completed his hat-trick in the 62nd minute, rounding the keeper before slotting the ball into an empty net.
Another loanee, Gerard Deulofeu, came off the bench and added the finishing touches 10 minutes from time.
Defending La Liga champions Atletico scored three second-half goals to beat Segunda B team L'Hospitalet in their first-leg clash.
Antoine Griezmann ghosted into the penalty area 20 minutes after coming on at half-time to head Diego Simeone's side in front from close range in the round of 32 tie.
Gabi's 81st-minute penalty doubled Atletico's lead before Cristian Rodriguez added a third goal for the visitors in stoppage time.
Barcelona also recorded a straightforward victory, trouncing third-tier side Huesca 4-0 away from home.
Ivan Rakitic was the driving force in Barca's midfield and his tremendous free-kick opened the scoring, before Andres Iniesta - playing his first match since October 25 due to a calf injury - grabbed his first goal of the season with an excellent finish.
Pedro effectively ended the game as contest with a fierce drive seven minutes before the break, and Rafinha made it four in the second half with his first Barca goal - albeit with the help of a huge deflection.
In other first-leg fixtures on Wednesday, Toche's 68th-minute equaliser earned hosts Deportivo La Coruna a 1-1 draw with Malaga.
Granada were 1-0 winners over 10-man Cordoba.