The Blues dominated proceedings for long periods of the match but were left stunned by goals in the very early and late stages of the match from Apoel, who endeavoured throughout.
The match signals a run of three games without a win for Carlo Ancelotti's side, whilst conceding an unheard of seven goals in that period.
The visitors got off to the best possible start with six minutes in the clock with a neat piece of play which had Blues skipper John Terry screaming for an offside flag that never came.
After some slick interplay on the left wing, Costas Charalambides squared to Marcin Zewlakow who beat the offside trap placed by Terry and partner Ricardo Carvalho.
Zelakow kept his cool to calmly roll the ball past stand-in goalkeeper Ross Turnbull, who was presented with a rare start by Ancelotti after Petr Cech's failings in the weekend defeat to Manchester City.
From then on it was all Chelsea, with Joe Cole and Yuri Zhirkov looking particularly dangerous in tandem down the left flank.
Cole thought he had brought his side level with a decisive header in the 12th minute from Florent Malouda's inswinging cross, but he was forced to cut his celebrations short when he noticed an offside flag which was raised instantly.
But the hosts did not have to wait much longer to get themselves on level terms as a trademark long-range thunderbolt from Michael Essien seven minutes later proved too hot to handle for visiting keeper Dionisios Chiotis.
Moments later, the Ghanian midfielder limped off with a suspected hamstring injury, but the disappointment of the loss was quickly forgotten when Didier Drogba fired his side in front on 26 minutes.
After receiving the ball from the impressive Gael Kakuta, whose mazy run through midfield created acres of space on the left wing, Zhirkov picked out the in-form Drogba who fired home with a low strike from 12 yards.
From then on the Blues were in complete control and it should have been 3-1 before the break as Kakuta's pinpoint pass found Cole who was left one-on-one with Chiotis. But the wideman's hesitance allowed Soares Paulo Jorge to get back and make a challenge to take the sting away from the shot.
A quiet second half which was marred by hopeful long-range shooting came to life in the last ten minutes as Chelsea were again denied a goal by the linesman's flag.
Substitute Fabio Borini's overhead kick was saved by Chiotis, before Terry's shot from close range was adjudged to be offside.
And Chelsea's frustration was compounded with just three minutes to go, as John Obi Mikel presented the ball to Apoel's top scorer Nenad Mirosavljevic.
The striker gladly accepted Mikel's offering by sprinting clear and sliding home past Turnbull to the delight of the vocal travelling support.
Cole had an opportunity to win the match for the Blues in stoppage time, but their unbeaten record in the group ensured top spot and a so-called easier draw in the Super 16 stage of the competition.