US State Department spokeswoman Heather Nauert said in a statement on Thursday that Washington would establish an "observer mission" to replace its representation at the Paris-based agency, according to presstv.ir.
"This decision was not taken lightly, and reflects US concerns with mounting arrears at UNESCO, the need for fundamental reform in the organization, and continuing anti-Israel bias at UNESCO," the statement said.
“US withdrawal will take effect on December 31, 2017. The United States will remain a full member of UNESCO until that time,” it added.
UNESCO, which has 195 member states, is known for designating world heritage sites such as Syria's Palmyra, the Grand Canyon in the US state of Arizona and twenty-two sites in Iran.
The head of UNESCO Irina Bokova voiced "profound regret" on Thursday over the US decision, calling it a "loss to multilateralism."
"I wish to express profound regret at the decision of the United States of America to withdraw from UNESCO," Bokova said in a statement.
The US also withdrew from the organization in 1984 during the administration of former US President Ronald Regan, claiming it was biased in favor of the former Soviet Union.
Former US President George W. Bush rejoined UNESCO in 2002. The US stopped funding the body in 2011, after the organization accepted Palestine as a member.
US President Donald Trump is also reportedly considering withdrawing the United States from the Geneva-based UN Human Rights Council (UNHRC), which his administration accuses of being biased against Israel.