The branch in the upscale Abu Rummaneh neighbourhood of Damascus is the last of seven KFCs in Syria to have shuttered.
"Closed. Please leave your number if you are interested in buying this establishment," a sign posted on the branch's window now reads.
KFC was the first US fast-food restaurant to set up shop in Syria in 2006, with Kuwaiti businessman Nasser Khurafi bringing the chain to the country.
It remained open despite the sanctions imposed against Syria by the United States in response to the regime's crackdown on an uprising that began in March 2011.
"The business was facing multiple problems" including in procuring supplies, a local businessman told AFP.
The conflict that began with an uprising against President Bashar al-Assad's regime has ravaged Syria's agricultural sector while fighting has made delivery of products to market increasingly difficult.
The violence has also caused the value of the Syrian pound to plunge and produced increasing poverty among Syrians, making the cost of a KFC meal beyond the reach of most.