The 3-1 defeat to Mechelen was Ferrera's first match since signing a new contract.
"With everyone looking forward to a new start after a difficult (last) season, the performance in the first game against KV Mechelen was surprisingly poor," the club said in a statement on their website (www.krcgenk.be) on Tuesday.
"On Monday night, we decided to immediately end our co-operation with Emilio Ferrera."
Ferrera, who took over from former Dutch international Mario Been in February, had his contract extended by two years at the end of last season.
The 47-year-old has been a regular on the Belgian coaching circuit for the last decade and also coached in Greece and the Middle East. Genk were Belgian champions in 2011.
(Reporting by Mark Gleeson; Editing by Stephen Wood)
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