Opened during the War of 1812 as Duplanty, McCall and Company spinning mill (and contemporaneous with nearby Breck's Mill,
CH19
), the three-story, water-powered stone factory briefly made fine cotton cloth and yarn but almost immediately switched to coarse goods in an attempt to compete with cheap British imports. The business failed in 1819. Later owners included Victor and E. I. du Pont as shareholders. A cotton-picking machine and dye vats occupied the basement; a carding machine stood on the first floor; and spinning mules and looms were located on the first and third floors. At one end, a small cupola atop a tower housed a bell. Surviving time sheets show that workers (32 percent female) toiled from dawn to eight in the evening, six days a week. By the 1840s, the mill was named for Senator Henry Clay, advocate for American industry. It was converted to the manufacture of metal kegs for powder in 1884.

As leading figures in the DuPont Company began planning the Hagley Museum in 1950, the mill was chosen as the interpretive centerpiece, to be gutted to the walls and have a steel and concrete interior inserted. Walter J. Heacock, director of exhibition buildings at Colonial Williamsburg, came in 1954, and elaborate displays were conceived (1955–1957, Walter Dorwin Teague Associates). A renowned industrial designer who had promoted Streamline Moderne style in the 1930s, Teague was famous for his trade-show exhibits for major corporations, including DuPont's at the World's Fair of 1939 in New York City (in a building by A. M. Erickson). His first-floor exhibits in Henry Clay Mill opened in May 1957 and featured an innovative “talking map” of the Brandywine Valley, possibly the first multilingual museum display in the United States. Miniature working models—marvelously complex and accurate—showed how mill technology worked. Today these exhibit spaces are rare surviving examples of modernist interior design in Delaware, worth preserving in themselves.