Irina Bokova said in a statement that the fighting was "putting at risk one of the most significant sites in the Middle East," as Islamic State fighters overran the north of the city.
"I reiterate my appeal for an immediate cessation of hostilities at the site," she added.
Palmyra's UNESCO-listed heritage site, including ancient temples and colonnaded streets, and its adjacent museum housing priceless artefacts, are in the city's southwest.
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Rami Abdel Rahman of the Syrian Observatory for Human Rights said IS fighters had seized roughly "a third" of Palmyra, the second time they have overrun northern Palmyra.
Syria's antiquities chief Mamoun Abdulkarim said hundreds of statues and artefacts from Palmyra's museum had been transferred out of the city but many others -- including massive tombs -- could not be moved.
Bokova called on the international community to do "everything in its power" to protect civilians in the city and "safeguard the unique cultural heritage of Palmyra".
"It is imperative that all parties respect international obligations to protect cultural heritage during conflict, by avoiding direct targeting, as well as use for military purposes," she said.