US Ambassador Nikki Haley said the UNESCO decision was an "affront to history" and "further discredits an already highly questionable UN agency."
"Today's vote does no one any good and causes much harm," said Haley in a statement.
The United States stopped funding the UN agency in 2011 after it admitted the Palestinians as a member-state, but it remains a member of UNESCO's 58-member executive board.
Haley said however that following the vote, "the United States is currently evaluating the appropriate level of its continued engagement at UNESCO."
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A committee of the UN's cultural arm voted 12 to three -- with six abstentions -- to give heritage status to Hebron's Old City.
The area includes the site known to Jews as the Tomb of the Patriarchs and to Muslims as the Ibrahimi Mosque.
Israeli Prime Minister Benjamin Netanyahu slammed the vote as "another delusional decision" but the Palestinian foreign ministry said UNESCO had recognized the right to register "Hebron and the Ibrahimi Mosque under Palestinian sovereignty.