Needing an unlikely win to have any chance of a Europa League berth, the Cypriots stunned Stamford Bridge with a sixth minute goal from Marcin Zewlakow.
The Group D leaders, who had previously conceded only two goals in five games, replied in the 19th when Michael Essien lashed in a swerving shot from 25 metres.
The Ghanaian hobbled off four minutes later with a leg injury that manager Carlo Ancelotti said would likely rule him out of Saturday's home Premier League match against Everton.
There was no stopping Chelsea however, who went 2-1 up through Didier Drogba in the 26th while temporarily down to 10 men before Frank Lampard came on as a substitute in a dominant first half.
Chelsea, already assured of top spot in the group, eased off in the second half and a glaring defensive error allowed APOEL to come back into the game with an 87th minute goal from substitute Nenad Mirosavljevic.
"The second half was not good, we have to do better," a scowling Ancellotti told Sky Sports television. "More concentration, more pressure, more intensity."
Drogba agreed: "We were not concentrating and we thought that 2-1 was going to be a good result but APOEL had to give everything if they wanted to believe," he said.
"I think we have to go into the changing room and try to collect what went wrong...this game was very frustrating because we had a lot of chances but I think we have to give more, play together and defend together," he added.
Chelsea, who had a goal disallowed in each half, gave French teenager Gael Kakuta his first start with Ancelotti hailing him as one of the best players on the pitch.
