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The Baltimore area had been inhabited by Native Americans since at least the 10th millennium BC, when Paleo-Indians first settled in the region. One Paleo-Indian site and several Archaic period and Woodland period archaeological sites have been identified in Baltimore, including four from the Late Woodland period. In December 2021, several Woodland period Native American artifacts were found in Herring Run Park in northeast Baltimore, dating 5,000 to 9,000 years ago. The finding followed a period of dormancy in Baltimore City archaeological findings which had persisted since the 1980s. During the Late Woodland period, the archaeological culture known as the Potomac Creek complex resided in the area from Baltimore south to the Rappahannock River in present-day Virginia.

The city is named after Cecil Calvert, 2nd Baron Baltimore, an Anglo-Irish member of the Irish House of Lords and founding proprietor of the Province of Maryland. The Calverts took the title Barons Baltimore from Baltimore Manor, an English Plantation estate they were granted in County Longford, Ireland. Baltimore is an anglicization of the Irish name Baile an Tí Mhóir, meaning “town of the big house”.

In the early 1600s, the immediate Baltimore vicinity was sparsely populated, if at all, by Native Americans. The Baltimore County area northward was used as hunting grounds by the Susquehannock living in the lower Susquehanna River valley. This Iroquoian-speaking people “controlled all of the upper tributaries of the Chesapeake” but “refrained from much contact with Powhatan in the Potomac region” and south into Virginia. Pressured by the Susquehannock, the Piscataway tribe, an Algonquian-speaking people, stayed well south of the Baltimore area and inhabited primarily the north bank of the Potomac River in what are now Charles and southern Prince George’s counties in the coastal areas south of the Fall Line.