Anecdotal evidence of the arrival of the first Armenians in America is widespread. One of the first accounts is of a 'Martin the Armenian,' who arrived in America in 1619 as a servant of Sir George Yeardley, the newly appointed Governor of the Virginia colony. Settled in Virginia, he became involved in tobacco and silk and was granted British citizenship, becoming, according to one source, "the first naturalized person on the American continent." Martin's tobacco trading brought him to England in 1622, where he won a legal case against the restriction of tobacco imports into Britain, and later became a full member of the Virginia Company of London, with the right to vote during meetings. His trail goes cold following the company's dissolution by Kina James I in 1624.

In 1653 two Armenian silk growers, sponsored by the English barrister and colonist Edward Digges, settled in the colony of Virginia in an attempt to develop the manufacture of silk in the Americas. Three years later, the Virginia House of Burgesses passed a resolution awarding four thousand pounds of tobacco to one of them to encourage him to remain in the colony and continue silk culture experiments.

With the help of Armenian guides and translators, numerous Americans traveled to Armenia in the mid to late 19th century, staying in towns such as Kharpert, Tokat, Erzurum, Kars and Gyumri. Research conducted by American missionaries uncovered many details of the persecution of Armenians by the Ottoman government and provoked a multitude of concerns and thoughts on how to change the situation and the desperate condition of Armenian Christians

By 1900 a significant number of American missionary stations had been set up in parts of Western Armenia and Cilicia Besides promoting Protestant values, American missionaries residing in Armenian-populated regions established schools and colleges to spearhead American education among their converts. The Euphrates College in Kharpert, st. Paul of Tarsus College in Aintab, Anatolia College in Marsovan, among others, were instrumental in educating a new generation of Armenians and bringing them closer to Western values. Many Armenians who had studied at American institutions in Western Armenia and the Levant later became graduates of American universities, such as Harvard, Yale, and Princeton.