Some of the United States's closest allies are among UNESCO's 195 members.
It notes that the official notification of this was given by UNESCO Director-General from Secretary of State Rex Tillerson.
Heather Nauert, US state department spokesperson, said on Thursday the US would establish an "observer mission" to replace its representation at the Paris-based agency.
Earlier this year, UNESCO triggered Israel's anger after it listed Hebron, a city in the occupied West Bank, as a world heritage site in the "State of Palestine".
Secretary of State Rex Tillerson gave formal notification of the U.S. withdrawal on the grounds of "continuing anti-Israel bias" and "mounting arrears".
At the time, Netanyahu said the "absurd" vote denied the Jewish connection to the city.
Travelers are likely to be most familiar with Unesco through its world heritage sites such as the Grand Canyon National Park and Yellowstone National Park in the US.
"Universality is critical to UNESCO's mission to strengthen worldwide peace and security in the face of hatred and violence, to defend human rights and dignity", she said in a statement.
In 2011 the USA cut its funding to the agency - slashing its budget by 22 percent - in protest at its decision to grant full membership to the Palestine.
But according to Nikki Haley, the US ambassador to the United Nations, the Trump administration found it to be a step too far when the agency decided this summer to designate "the Old City of Hebron and the Tomb of the Patriarchs as part of Palestinian territory".
Francois Heisbourg, chairman of the International Institute for Strategic Studies, said the decision was probably motivated by Trump's desire to send a message of support to Israel and underlined his "America First" policies.
The outgoing head of UNESCO, Irina Bokova, called the U.S. withdrawal a "loss to multilateralism", while UN Secretary General Antonio Guterres said through a spokesman that he "regrets this development deeply". This is a loss to the United Nations family. Permanent Representative to the UN Nikki Haley has repeatedly denounced these actions, and said the US was "evaluating" whether or not it should continue as a member of the organization.
The U.S. told Bokova it intends to stay engaged as a non-member "observer state" on "non-politicized" issues, including the protection of World Heritage sites, advocating for press freedoms and promoting scientific collaboration and education. In 2002, George W Bush joined UNESCO again, and in 2011, Barack Obama cut most U.S. funding to UNESCO due to the organization's recognition of Palestine. Under the Reagan Administration, the U.S. quit UNESCO in 1984, at the time accusing the agency of a pro- Soviet Union bias.