"I condemn with the strongest force the destruction of the site at Nimrud," Irina Bokova said in a statement.
She said she had already spoken with the heads of the UN Security Council and International Criminal Court on the issue.
"We cannot remain silent. The deliberate destruction of cultural heritage constitutes a war crime. I call on all political and religious leaders in the region to stand up and remind everyone that there is absolutely no political or religious justification for the destruction of humanity’s cultural heritage."
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IS "assaulted the historic city of Nimrud and bulldozed it with heavy vehicles," Iraq's government said on Thursday.
An antiquities official said the destruction began after noon prayers on Thursday and that trucks may have been used to haul away artefacts.
"UNESCO is determined to do whatever is needed to document and protect the heritage of Iraq and lead the fight against the illicit traffic of cultural artefacts, which directly contributes to the financing of terrorism," said Bokova.
"At stake is the survival of the Iraqi culture and society."