Clara Barton was born on December 25, 1821, in Oxford, Massachusetts, and began teaching at age fifteen. She became one of the first women to work for the federal government, holding a position at the U.S. Patent Office in Washington, D.C. When the Civil War erupted in 1861, Barton nursed forty wounded soldiers from the 6th Massachusetts Militia after the Baltimore Riot, the first bloodshed of the conflict. By 1862 she had gained permission to work on the front lines, distributing supplies, cleaning field hospitals, and dressing wounds at battles including Cedar Mountain, Second Bull Run, Antietam, and Fredericksburg. She treated both Union and Confederate soldiers. In 1864 she was formally appointed superintendent of nurses for the Army of the James. After the war, at President Abraham Lincoln's request, she established a bureau of records to locate missing soldiers, eventually helping to identify nearly 13,000 Union graves at the Andersonville prisoner-of-war camp.

The story of the Glen Echo house is inseparable from the story of the Johnstown Flood. When a catastrophic dam failure killed more than 2,200 people in Johnstown, Pennsylvania in 1889, Barton led one of the first major Red Cross disaster relief operations in American history. Afterward, the emergency buildings constructed for survivors were dismantled, and the lumber was transported to Washington via the Chesapeake and Ohio Canal to avoid flooding the local timber market in Johnstown. Barton stored the wood on a lot she owned in the capital until 1891, when construction began on land donated by Edwin and Edward Baltzley, who were developing a Chautauqua assembly at Glen Echo. Dr. Julian B. Hubbell, the first field agent of the American Red Cross, designed the house. The original structure featured a massive stone front in keeping with the surrounding Chautauqua buildings.

When Barton moved into the house permanently in 1897, the central stone facade was dismantled, creating flanking stone towers capped with pointed roofs that gave the deep, narrow structure a distinctive silhouette. Inside, the house is deliberately functional. Despite its massive size, it is sparely detailed and furnished for utility rather than elegance. The interior layout was designed to resemble a Mississippi River steamboat, with 36 rooms and 38 closets arranged in three tiers facing a central gallery lit by clerestory windows of colored glass. The house served double duty as both Barton's personal residence and an early headquarters of the American Red Cross, where she directed relief efforts for floods, hurricanes, and famines until her death in 1912 at age ninety.

Congress designated the Clara Barton House as a National Historic Landmark in 1965 and placed it on the National Register of Historic Places in 1966. It became a National Historic Site in 1974. The National Park Service acquired the property from the Friends of Clara Barton in 1975 and restored eleven rooms, including the Red Cross offices, parlors, and Barton's bedroom, dedicating the site in 1981. Today the house is managed by the George Washington Memorial Parkway, a unit of the National Park Service, and protects nine acres of land. The house reopened to the public in 2022 after being closed during the COVID-19 pandemic, though the second and third floors remain closed due to structural concerns. The site preserves not only the home of a remarkable woman but the physical material of her life's work, walls literally built from the wreckage of the disasters she spent her career confronting.