Main Street began as a Native American trail that paralleled the Great Miami River. The trail took a shortcut across the east bend of the river thus creating the route that would become the center of the future City of Piqua. This early trail became part of a military route known as the Detroit Trail. General George Rogers Clark in 1782 and General "Mad" Anthony Wayne in 1794 used the trail during their campaigns against area Native American tribes. European-Americans began to settle in the area at the turn of the nineteenth century. Two of these early settlers, John Manning and Matthew Caldwell decided that the most profitable venture in the area would not be raising corn but selling lots in a new village. They hired Armstrong Brandon in 1807 to survey 101 lots and lay out a series of streets for the new settlement of Washington (later renamed Piqua). Brandon centered the new village on the old north-south Detroit Trail and surveyed it as Main Street.
By 1808-1909, county roads were connecting Main Street to the rest of the Miami Valley. The Piqua-Troy Road (County Road 25-A) dead ended at Main Street on the south end and the Piqua-Fort Loramie Road (County Road 25-A) did the same thing on the north end. Main Street was also connected to another, more direct road to Fort Loramie (State Route 66), at the present intersection of Main Street and Riverside Drive. Main Street was a dirt road which became extremely muddy during the wet seasons and very dusty during the summer. Heavy traffic also led to rutting down both sides of the street. During the first part of the nineteenth century, the street was routinely scraped by dragging a heavy beam over the dirt to cut down on ruts and unevenness caused by the wear and tear of horses and iron-clad wagon wheels. By the 1880's, oiling the street became common to cut down on dust and diminish the depth of mud. The city would finally solve the issues of dust, mud and ruts in 1895 when Main Street was covered with thick brick pavers. During the early twentieth century, asphalt was used to cover the unevenness of the bricks and later a new cement and asphalt street was laid.
During the 1820's and 1830's, retail shops, taverns, public halls and mills were build on Main Street right next to the community's first brick homes. Piqua's government took center stage in 1845 with the erection of the first Town Hall on the east side of the Public Square facing Main Street. The 1860 "Commercial Block", located on the northwest corner of the public square, was the first large scale retail building on Main Street. Main Street's physical appearance changed as department stores began building three and four story brick and stone structures. Benkert's was completed in 1899 (200 block), Maneer-Freeman (later Penney's) in 1907 (400 block) and Brown's in 1908 (300 block). The Second Renaissance Revival Style began to dominate downtown with the construction of the Piqua National Bank (1898) on the northwest corner of Main and High Streets (public square), the Orr-Flesh Building (1903) on the northwest corner of Main and Ash Streets and the Buntin-Young Building (1903) just north of the Orr-Flesh Building. The last two major structures to be completed on Main Street were the Ohio Theater (1928) on the southwest corner of Main and Greene Streets and the Kresge Building (1932) on the southwest corner of Main and Ash Streets.
Main Street has served as a transportation hub with north-south road travel, canal traffic (a half block to the east) and a crossroads with the Pennsylvania Railroad. The street has also been the scene of parades, political rallies, community celebrations, holiday remembrances and even on occasion social strife (KKK rally, strikes and civil rights sit-ins). Main Street continues into the twenty-first century as the heart of the Central Business District.