In a statement, the club said: "APOEL announces it is ending its cooperation with coach Mick McCarthy".
The former Ireland Manager was under increasing pressure in Cyprus.
APOEL lost the game 2-1 to rivals Doxa, with Byrne entering the fray in the 86th minute of the game.
The 61-year-old in November signed a deal until 2022 but has been shown the door just eight weeks into his reign.
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Apoel have now had 13 permanent coaches since 2015.
McCarthy had been due to remain in charge of the Boys in Green until the end of the Euro 2020 campaign, before being replaced by Stephen Kenny.
He led Ireland to the 2002 World Cup with the team advancing from their group only to be eliminated by Spain in a penalty shootout.
Republic of Ireland worldwide Jack Byrne made his debut in the defeat, coming on as a 85th minute substitute having only completed his move to the club earlier this week.
It could leave the recently signed Republic of Ireland global Jack Byrne nervously anticipating what future he might have in Cyprus, just two days after confirming his free-transfer from Shamrock Rovers to the Cypriot outfit, much on the recommendation of the now ousted McCarthy.