In 1708, Queen Anne of England gave the Hardenburgh Patent to Johannes Hardenbergh and his associates.

In 1763 Harmanus DuMond was deeded 75 acres (30 ha) "opposite Margaretville" by Chancellor Livingston.

[4][5][6][7] A 1765 map by Will Cockburn shows a road from Marbletown to Pakatakan (near present-day Margaretville and Arkville).

[8] In the 1770s, the original settlers paid "one hundred forty-nine pounds and 19 shillings" to American Indians for the land.

In June 1778, a combined force of Tories and Indians led by Joseph Brant raided the valley, including the Margaretville area.

[10] Before the settlers were driven from their homes, they were given a timely and friendly warning by an Indian named Tunis and returned to the Hudson Valley.

Dr. Poldino was also made first postmaster in June 1848, when Margaretville was designated as a post office station.

In 1904, Clarke A. Sanford bought the Margaretville Messenger and changed the name to the Catskill Mountain News.

In 1925, Dr. Gordon Bostwick Maurer moved to the community, and his village home quickly became a "veritable hospital".

On October 21, 1930, the Margaretville Hospital was incorporated and was built using a two-story white farmhouse near the current high school.

[11] Margaretville was the hometown of Dr. Orvan Hess, inventor of the fetal heart monitor and one of the first doctors to successfully treat a patient with penicillin.

This caused a drop in local trade, but the project did give the village its own sewer system.

Many buildings sustained structural damage, and over 100 residents had to take shelter in the village fire station.

[15] On April 24, 2007, Travis Trim of North Lawrence, New York, shot a state trooper, who was saved by his bulletproof vest.

Several surrounding areas including Margaretville and its school were used in the zombie film, The Dead Don't Die,[21] starring Bill Murray, Adam Driver, and Selena Gomez.