As early as the 1650s, colonists forced native peoples onto reservations, plots of land set aside specifically for them. By 1700, the number of native peoples that lived in Maryland had declined because of disease and migration out of the area. Many, like the Piscataway, left Maryland because it had become a colonial world, where Indians no longer felt at home.

The archaeological evidence, such as arrowheads, pottery pieces, and bone fragments, indicate that Native Americans once used the land that became London Town to hunt, perhaps even clearing trees to create pastures and lure game, which was their main source of meat. Their clothing was made primarily from animal skins. They might have only stayed for a short time, perhaps to fish and process oysters. However, deer bones, ceramics, pecking stones, and grinding stone fragments suggest that these Late Woodland people spent considerable time at the site, and may have lived there seasonally. They may have grown crops such as corn, squash, and beans, which were so essential to their food supply. While archeologists have not yet found evidence of structures or storage pits, the artifacts recovered near London Town show that it was an area well-traveled by native peoples.