The Nacochtank villages which dotted the south side of the Anacostia River were busy trading sites for Native Americans in the region.

[12][14][15] European settlement first occurred in the area in 1662 at Blue Plains (now the site of the city's sewage treatment plant just to the west of the modern neighborhood of Bellevue), and at St. Elizabeth (now the site of St. Elizabeths Hospital psychiatric hospital) and Giesborough (now called Barry Farm) in 1663.

[16] In 1663, Lord Baltimore granted ownership of the majority of the area on the south bank of the Anacostia River to George Thompson.

[17] In 1795, real estate speculator James Greenleaf purchased most of what is now the Anacostia Historic District from the federal government.

[16] Although Greenleaf was bankrupted in the Panic of 1796–1797,[18] a few homes dotted the shores of the eastern bank of Anacostia River in what is now the historic district.

Consequently, in 1818, the privately owned "Upper Navy Yard Bridge" was built over the Anacostia River at 11th Street SE.

The bridges shifted currents and slowed the river's flow, and within a decade, extensive flats had built up along the shore.

[6][23] Dr. Arthur Christie, a wealthy Englishman, purchased 50 acres (20.25 hectares) of land on the north side of Harrison Street and named his estate Fairlawn.

[12] Lewin Talburtt built a spectacular 21-room mansion, "Mont View," on what is now Mount View Place SE; his son, George Washington Talburtt, lived there for many years (although it is an apocryphal story that John Howard Payne composed the song Home!

[16] Van Hook had hoped to attract Navy Yard workers to buy and build in the Uniontown development.

After the First Battle of Bull Run, Northern military leaders realized Washington, D.C., was relatively undefended and quickly began building a ring of forts around the city.

The Union Land Association went bankrupt in the Panic of 1873, and Van Hook was forced to sell Cedar Hill.

[12][22][23] The mansion was purchased by Frederick Douglass in 1877, who defied the whites-only covenant governing the subdivision in buying the property.

[15][34] In 1920, local African-American Roman Catholics constructed Our Lady of Perpetual Help church on land formerly owned by physician J.C.

[36] In 1867, Major General Oliver Otis Howard, commissioner in charge of the Bureau of Refugees, Freedmen and Abandoned Lands, purchased John Barry's farm immediately southwest of Uniontown/Anacostia, subdivided the property, and sold small lots at rock-bottom prices to formerly enslaved people (establishing the neighborhood of Barry Farm).

[16][37][38] Businessman Arthur Randle purchased the John Jay Knox farm south of St. Elizabeths Asylum and established the new subdivision of Congress Heights in 1890.

[30] He purchased undeveloped land south of Pennsylvania Avenue SE and created another new subdivision, Randle Highlands[30][39] Uniontown/Anacostia, Barry Farm, Congress Heights, and Randle Highlands remained isolated from one another, and most of the land between them was undeveloped until World War II.

[23] The oppressive need for housing during the war, brought by a massive influx of federal workers to the capital, led to extensive development of the region and the linking of the area encompassed by the Anacostia Historic District with other parts of Southeast D.C.[23] Only 16 percent of the homes in Southeast Washington below Pennsylvania Avenue SE were built before 1940, but 38 percent were built after 1950.

Historic Preservation Office provided $300,000 in $35,000 individual grants to Anacostia residents to help them restore, renovate, and rehabilitate their homes.