The Icon of The Virgin Mary, which is credited with miracles, was reported missing on Friday at the Orthodox Christian monastery of Elona, near the town of Leonidio, south-west of Athens.
"This is the worst thing that could happen to us, our church and our religion," said Metropolitan Bishop Alexandros of Mantineia and Kynouria.
He described the icon, which measures 50 by 40 centimetres, as "priceless."
It's believed the robbers used climbing equipment to reach the monastery, which is built into the face of a cliff.
The robbers may have been hiding on the monastery grounds before it closed for the evening Thursday, Bishop Alexandros said.
Thousands of worshippers visit the icon each year, most around August 15, an Orthodox Christian religious holiday in honour of the Virgin Mary.