Cesspool Pumping in Glen Cove, NY.

Succeeding cultures of indigenous peoples had lived in the area for thousands of years. At the time of European contact, bands of the Lenape (Delaware) nation inhabited western Long Island, the areas of New York and New Jersey around the harbor, and along the coast through present-day Pennsylvania and Delaware, as well as along the Delaware River. They spoke an Algonquian language. By 1600 the band inhabiting this local area was called the Matinecock after their location.

Glen Cove was used as a port by English migrants from New England and named Moscheto before 1668. On May 24, 1668 Joseph Carpenter of Warwick, Rhode Island purchased about 2,000 acres (8.1 km²) of land to the northwest of the Town of Oyster Bay from the Matinecock. Later in that year, he admitted four residents of Oyster Bay as co-partners in the project: brothers Nathaniel, Daniel, and Robert Coles; and Nicholas Simkins. The five young men named the settlement Musketa Cove Plantation, musketa meaning place of rushes in the Lenape language.

In the 1830s, steamboats started regular service on Long Island Sound between New York City and Musketa Cove, arriving at a point still called The Landing. As Musketa was negatively associated with mosquito, in 1834 residents changed the name to Glen Cove; this was said to be taken from the misheard suggestion of Glencoe, meaning Glencoe, Scotland.