According to the United Nations, a satellite image confirms that Palmyra’s Temple of Bel in northern Syria has been destroyed.
There had been earlier reports of an explosion at Palmyra’s main temple, which is held by ISIS militants.
Syria’s antiquities chief had earlier said the basic structure of the 2,000-year-old site was intact.
However, UN satellite analysts UNOSAT say the image shows almost nothing remains.
On August 31, Maamoun Abdul Karim, the head of the Syrian Department of Antiquities and Museums, had said the Temple of Bel suffered a large explosion, but that he believed most of the site had remained intact.
Witnesses had struggled to get close to the site to confirm the extent of the damage.
ISIS has previously targeted historical sites in areas under its control in Iraq and Syria, regarding their ancient temples and sculptures as heretical.
The sale of looted antiquities is one of the group’s main sources of funding. It has also been accused of destroying ancient sites to gain publicity.
Authorities removed hundreds of statues and priceless objects before ISIS tightened its grip on Palmyra earlier this year.
Last week, it was confirmed that another site at Palmyra, the Temple of Baalshamin, had been blown up.
UNOSAT released satellite images showing the extent of the damage, proving that parts were heavily damaged or completely destroyed.
ISIS militants seized control of Palmyra in May, sparking fears for the World Heritage site.
Earlier this month the group murdered 81-year-old Khaled al-Asaad, the archaeologist who had looked after the Palmyra ruins for 40 years.
The world-famous Greco-Roman ruins of Palmyra are in the desert north-east of the Syrian capital, Damascus.
The Temple of Bel is dedicated to the Palmyrene gods and was one of the best-preserved parts of the ancient city of Palmyra.
Syrian government forces have sought to drive ISIS out of the Palmyra area in recent months and there has been fierce fighting in nearby towns.