Substitute Frank Acheampong scored with his first touch to seal a 1-0 second-leg win for Anderlecht as APOEL were beaten 2-0 on aggregate in the last 16.
Nicolae Stanciu's away goal had secured victory in a tight first leg, but Anderlecht were more convincing in asserting their dominance back in Brussels, although they were made to wait for the breakthrough.
Early openings came and went for Lukasz Teodorczyk and APOEL were fortunate to head into the interval still level as goalkeeper Boy Waterman was worked time and time again.
The visitors' improvement in the second half was minimal, though, and Acheampong was introduced from the bench after 64 minutes as Anderlecht sought to finally kill off the tie.
And the Ghana international's impact was immediate as he pounced on a loose ball in the box just seconds later to convert and deservedly send Rene Weiler's side through.
Lukasz Teodorczyk twice squandered big chances for Anderlecht in the opening four minutes, first straying offside as Youri Tielemans squared for a simple tap-in and then shooting straight at Waterman from Sofiane Hanni's incisive pass.
Waterman was rather less impressive as he fumbled Andy Najar's curler behind and he again spectacularly blundered in trying to gather the ball from Stanciu's drive as the visitors failed to clear a free-kick from which Uros Spajic had somehow screwed across the face of goal.
Anderlecht kept going and Waterman was fortunate to see Stanciu side-foot straight into his arms after Najar and Hanni had combined on the left to create the next golden opportunity.
Another wonderful flowing move on the same flank allowed Stanciu space to cross for Teodorczyk, but the Poland international directed his powerful header wide of the left-hand post.
Although Waterman was required to parry away Najar's low strike moments before half-time, the pattern of play was more balanced after the break as Pieros Sotiriou and Lorenzo Ebecilio snapped APOEL's first notable efforts off target.
Teodorczyk missed another headed chance, too, and Waterman scrambled across his line to stop Hanni's shot, but the deadlock was finally broken with 25 minutes remaining.
Hanni drove into the area on the left and delivered a centre that Waterman could only help towards the waiting Acheampong, who had the simple task of converting into an empty net.
APOEL rallied, with Ruben Martinez saving well from Kostakis Artymatas, but the pressure came too late for the visitors as they crashed out.