The Thirteen Colonies that would become the United States had little understanding of isolationism: most colonists knew of no other life except that of nationalist Europe and willingly accepted both the protection and complications of being a British colony. Thomas Paine is generally credited with instilling the first isolationist ideas into the American body politic; his work Common Sense contains many arguments in favor of avoiding alliances. These ideas introduced by Paine took such a firm foothold that the Continental Congress struggled against forming an alliance with France and only agreed to do so when it was apparent that the war for independence could be won in no other manner.

George Washington's farewell address set an isolationist tone that would not soon fade: "The great rule of conduct for us, in regard to foreign nations, is in extending our commercial relations, to have with them as little political connection as possible. Europe has a set of primary interests, which to us have none, or a very remote relation. Hence she must be engaged in frequent controversies the causes of which are essentially foreign to our concerns. Hence, therefore, it must be unwise in us to implicate ourselves, by artificial ties, in the ordinary vicissitudes of her politics, or the ordinary combinations and collisions of her friendships or enmities."

President Thomas Jefferson affirmed the ardent isolationism of the young country in his inaugural address: "peace, commerce, and honest friendship with all nations, entangling alliances with none."

The isolationist torch was still burning strong in 1823 when President James Monroe articulated what would come to be known as the Monroe Doctrine: "In the wars of the European powers, in matters relating to themselves, we have never taken part, nor does it comport with our policy, so to do. It is only when our rights are invaded, or seriously menaced that we resent injuries, or make preparations for our defense."

Indeed, the United States managed to maintain a state of political isolation throughout the 19th century and the first part of the 20th century. Few nations have been able to maintain such a stance for such a lengthy period of time. Historians have posited that this is largely due to a geography that is both detached and distant in relation to that of Europe.

The beginning of the 20th century saw German and Japanese imperialism challenge and later largely put an end to feelings of content isolationism enjoyed by the United States. The acquisition of the Philippine Islands during the Spanish-American War put U.S. interests in to the western Pacific Ocean, squarely in the sights of Japan. The U.S. failed to perceive threats made against its unencumbered position. It took Germany's unrestricted submarine warfare during World War I to shake the neutral stance that the U.S. had cherished for so long. When the war ended, the U.S. was quick to leave behind its "entangling alliances;" both the Treaty of Versailles and the League of Nations found little congressional support.

The time between the World Wars saw a resurgence in isolationism in the United States. After the war broke out in Europe, such Americans as Charles Lindbergh, Gerald P. Nye and Rush D. Holt prominently advocated U.S. neutrality.

Japan's 1941 Attack on Pearl Harbor effectively dashed any hopes of the U.S. further maintaining isolationism, as suddenly it put the U.S. into World War II. The sanguine effects of geopolitical alliance did not evaporate with Allied victory: in contrast, the developing Cold War would make them more desirable than ever. Today, the United States is far removed from its history of isolation. Through the United Nations, defensive agreements are in place with forty-four sovereign states.

A number of individuals in the contemporary U.S. are active in promoting a return to an isolationist foreign policy. These include progressives such as Ralph Nader, conservatives such as Pat Buchanan, and libertarians such as Justin Raimondo.