Abundance peaks in microscopic materials, including meltglass, microspherules, Ni, Ir, and Pt have been found in Native American Hopewell-age cultural strata. This discovery includes micrometeorites (possibly pallasites) recovered from heavily burned strata in two Hopewell villages. This evidence suggests that a prehistoric cosmic airburst/impact event occurred in the Ohio River valley. The peaks in these exotic materials only occur within a dark, charcoal-rich burn layer containing a wide range of Hopewell artifacts, and they are not found above or below the layer. Transgenerational oral histories and possibly two unique airburst-shaped Hopewell earthworks at or near the epicenter suggest that Native Americans living in the Ohio River valley may have been eyewitnesses to the impact event. AMS radiocarbon ages (n = 15) obtained directly from cultural and geological contexts indicate that the airburst/impact event occurred within a 70-year window from 1640-1570 cal BP. The Hopewell culture existed from ~2100-1500 cal BP and suffered a severe decline beginning ~1650 cal BP, suggesting that the proposed impact event occurred near the end of that span. After the proposed event, the hallmarks of the Hopewell culture, such as monumental landscape architecture, the largest geometric earthen enclosures in the world, intricate hilltop water management systems, massive burial mounds, and extensive ceremonial centers, were no longer constructed in the area impacted by the airburst. We propose that this cosmic airburst/impact event catalyzed the economic and sociopolitical decline and reorganization of the Hopewell cultural complex in the Ohio River valley for villages directly affected by the proposed airburst.