[2] The town was named after the local indigenous tribe and previously thought to mean "small river" in English.

The first known European to settle in the area was a trapper by the name of Christoffel "Kit" Davits,[6] who bartered with the Esopus people, a branch of the Lenape.

[7] The Cumming-Parker House, Esopus Meadows Lighthouse, Col. Oliver Hazard Payne Estate, Poppletown Farmhouse, and Reformed Protestant Dutch Church of Klyne Esopus Holy Cross Monastery are listed on the National Register of Historic Places.

In the early 19th century, Esopus was a popular summer residence for wealthy American families such as the Astors, Durkees, Paynes, Rockefellers, Smiths, Tiffanys and Whitneys, who built architecturally significant mansions and hunting lodges on the west bank of the Hudson River, across from the Vanderbilt and Roosevelt estates on the east bank.

Historical figures and celebrated people who have lived in Esopus include naturalist John Burroughs; financier Harry Payne Bingham; abolitionist Sojourner Truth; 19th-century U.S. politician George W. Pratt; Standard Oil treasurer Colonel Oliver Hazard Payne; business leader and president of Avco Corporation Raymond Rich; the Smith Brothers, who invented the first cough drops in America; Saint Frances Xavier Cabrini (patron saint of immigrants); Major Gen. Daniel Butterfield, who founded the American Express Company and wrote "Taps" in 1862; Eugene R. Durkee, who made a fortune in spices and salad dressings and whose West Park summer mansion became part of the Christian Brothers monastery; John Jacob Astor III; boxing champion Floyd Patterson who attended Wiltwyck School for Boys in West Park; and Alton Brooks Parker, a lawyer and judge who ran for U.S president as the 1904 Democratic party nominee, losing to incumbent Theodore Roosevelt.

On January 9, 1946, a photo appeared in the Kingston Daily Freeman, with a caption reading, "The local UNO Committee mapping a tentative itinerary for the Sub-Committee of the United Nations Organization (UNO) was impressed with the view shown above from Camp Chi-Wan-Da on the River road between Port Ewen and Ulster Park."

Many local property owners organized to oppose the proposed UN headquarters, however, fearing eminent domain.

Ultimately, a donation of more than eight million dollars by John D. Rockefeller Jr. for 16 acres of land in Manhattan provided the UN with its current headquarters in 1948.

The Rondout Creek marks the northern town line, while the Wallkill River defines the western border.

[10] Hussey Hill is part of the Marlboro Mountains, which run roughly north to south through the central and eastern sections of Esopus.

The town's government is made up of a supervisor, four council members, two justices, a highway superintendent, a clerk, and a tax collector.

Into the early 1950s, the New York Central was running three trains a day six days a week through the town, with stops, heading north: West Park, Esopus, Ulster Park and Port Ewen, from Weehawken, New Jersey to either Kingston or Albany.