Favourites progress to semis
Cristiano Ronaldo opened the scoring for Real Madrid, tapping home Marcelo's cross after a flick-on from Gonzalo Higuain.
Kaka added a second goal against APOEL with a sensational long-range effort.
Cristiano Ronaldo scored his first free-kick this season to put Real 3-0 up; the Portuguese has now netted 49 in all competitions this term.
Gustavo Manduca ensured APOEL left the Bernabeu with something after netting the first of the minnows' two consolation goals.
Angel Di Maria put the final nail in the APOEL coffin with Real's fifth goal of the game, a delectable chip to seal a semi-final clash with Bayern Munich.
Frank Lampard kept his cool to put Chelsea ahead against Benfica from the penalty spot after Javi Garcia fouled Ashley Cole.
Benfica were then left with a mountain to climb as captain Maxi Pereira was deservedly given his marching orders before half-time after earning a second booking.
Javi Garcia atoned for earlier giving away a penalty by heading Benfica level to give Chelsea a nervy final few minutes.
Substitute Raul Meireles eased Chelsea's nerves with an injury-time winner, a satisfying goal for the midfielder after he was barracked by Benfica fans in the first leg.
A 3-1 aggregate victory secured Chelsea's passage to the Champions League semi-finals, where a clash with reigning European champions Barcelona awaits.