During the American Revolutionary War, the property was the home of Isaac Van Wyck. However, because of its strategic location with regard to the Hudson River and major roads, the Old Albany Post Road (later US 9) running north–south and the road running east–west (later NY 52 and Interstate 84), it was requisitioned by the Continental Army. The building became the headquarters of the Fishkill Supply Depot, which was created on the orders of George Washington in 1775. The Fishkill Supply Depot was the major logistical center for the Revolutionary War in the north.

The depot was a military camp and storage yard which became the main provider of artillery and food for about 4,000 troops stationed in the area to prevent the British forces from passing New York City and capturing the Hudson Valley (the latter a major strategic goal of the British at the beginning of the American Revolutionary War). 70 acres (28 ha) of land surrounding the house were used for a large encampment of over 2,000 soldiers and many facilities such as an artillery park for repairing cannons, a blacksmith shop, barracks, a storehouse, and stables were set up.

Thousands of Continental troops, militia, and their families lived at the Depot complex until April 1783. Its position in the Hudson River Valley prevented enemy advances.

It served as headquarters to General Israel Putnam and was visited by revolutionary leaders such as George Washington, the Marquis de Lafayette, Friedrich Wilhelm von Steuben, Alexander McDougall, Alexander Hamilton, and John Jay. Inside the house, courts-martial were held in the home's parlor. Although under British surveillance, the Depot was never attacked, hundreds died there of wounds, hypothermia, dysentery, and smallpox. Periods of starvation were also endured by troops during the Depot's seven years of service. It is the largest burial ground of American Revolutionary War soldiers identified in the United States.