Los Blancos entered the match knowing that a victory would guarantee their place in the knockout round - eliminating Borussia Dortmund in the process - and the European champions ran riot on the night.
Real Madrid were without captain Sergio Ramos after the centre-back suffered a broken nose during the 0-0 draw with Atletico Madrid at the weekend. Nacho was the player to come into the back four, while Marco Asensio and Lucas Vazquez took the places of Isco and Casemiro.
The visitors had a chance to make the breakthrough inside two minutes when Benzema picked out Ronaldo with a deep cross, but the Portuguese saw his powerful effort saved by APOEL goalkeeper Nauzet Perez.
APOEL's first attempt of the match arrived in the seventh minute when Roberto Lago struck one from outside the box, but it was a fairly comfortable save for Kiko Casilla, who was again deputising for Keylor Navas.
The hosts were not lacking in confidence in the early exchanges as they continued to commit players forward, and Vinicius struck one over the Real Madrid crossbar in the 16th minute following a smart exchange of passes.
Ronaldo sent a long-range free kick wide of the APOEL post in the 21st minute as the score stayed level, but the visitors took the lead less than two minutes later when Luka Modric's volley ended up in the back of the net.
Modric's effort had plenty of weight behind it, but APOEL goalkeeper Perez perhaps should have done better.
The home side had a decent chance to level just before the 30-minute mark when Sallai met a cross from the right, but the number 20 sent his header just over Casilla's crossbar.
Real Madrid were the team firmly on the front foot, however, and they doubled their lead in the 39th minute when Benzema collected a through pass from Toni Kroos before finding the bottom corner with a super finish.
It went from bad to worse in the 41st minute when Nacho reacted first to a header from fellow centre-back Raphael Varane, and the Spaniard managed to acrobatically turn the ball past the onrushing Perez.
Madrid were not finished in the first half, however, and scored their fourth in stoppage time when a quick counter-attack saw Ronaldo slide a fine pass into Benzema, who could not pass up the chance to tap into the back of the net.
Ronaldo then got his name on the scoresheet in the 49th minute when he headed a Marcelo cross into the back of the net as Real Madrid made it 5-0 early in the second period.
Ronaldo should have made it six in the 52nd minute after a wonderful exchange with Benzema, but the Portuguese just dragged his effort wide of the near post.
The number seven doubled his tally in the 54th minute, however, as he hooked into an empty net after Benzema had beaten APOEL goalkeeper Perez to a loose ball in another disaster moment for the home side.
Dani Ceballos, Theo Hernandez and Borja Mayoral came off the Real Madrid bench in the period that followed as Zidane took the chance to hand minutes to three players that have struggled for league action this season.
Asensio forced Perez into a smart save 20 minutes from time as the visitors looked for a seventh, before Mayoral just failed to connect on a low cross from Hernandez in the 82nd minute.
Both teams had chances to add to the scoring late on, but six was how it finished as Real Madrid put their La Liga troubles aside to book their spot in the last-16 stage of the Champions League.
Real Madrid, who will finish second in Group H behind Tottenham Hotspur, will end their campaign at home to Dortmund early next month. Meanwhile, APOEL, who can still finish third in the section, will travel to Tottenham.