Archaeological evidence indicates Native Americans settled in the area at least 4000 years ago, around the Anacostia River. Early European exploration of the region took place early in the 17th century, including explorations by Captain John Smith in 1608. At the time, the Patawomeck (loosely affiliated with the Powhatan) and the Doeg lived on the Virginia side, as well as on Theodore Roosevelt Island, while the Piscataway (also known as Conoy) tribe of Algonquians resided on the Maryland side. Native inhabitants within the present-day District of Columbia included the Nacotchtank, at Anacostia, who were affiliated with the Conoy. Another village was located between Little Falls and Georgetown, and English fur trader Henry Fleet documented a Nacotchtank village called Tohoga on the site of present-day Georgetown.
The first colonial proprietors of land in the present-day District of Columbia were George Thompson and Thomas Gerrard, who were granted the Blue Plains tract in 1662, along with Saint Elizabeth, and other tracts in Anacostia, Capitol Hill, and other areas down to the Potomac River in the following years. Thompson sold his Capitol Hill properties in 1670, including Duddington Manor, to Thomas Notley; The Duddington property was handed down over the generations to Daniel Carroll, of Duddington. As European settlers arrived, they clashed with the Native Americans over grazing rights. In 1697, Maryland authorities built a fort within what is now the District of Columbia, and two years later, the Conoy relocated to the west, near Point of Rocks.
Georgetown was established in 1751 when the Maryland Legislature purchased sixty acres of land for the town from George Gordon and George Beall at the price of £280, while Alexandria, Virginia was founded in 1749. Situated on the fall line, Georgetown was the farthest point upstream to which oceangoing boats could navigate the Potomac River. Gordon had constructed a tobacco inspection house along the Potomac in approximately 1745. Warehouses, wharves, and other buildings were added, and the settlement rapidly grew. The Old Stone House, located in Georgetown, was built in 1765 and is the oldest standing building in the District. It did not take long before Georgetown grew into a thriving port, facilitating trade and shipments of tobacco and other goods from colonial Maryland.