Despite the importance of understanding the effect of land use on floodplains in eastern North America, few studies have directly addressed the possibility and extent of prehistoric indigenous land use on floodplain development. Here we report geoarchaeological evidence of increasing floodplain sedimentation and prehistoric land-use intensification in the Delaware River Valley (eastern United States) during the Medieval Climate Anomaly–Little Ice Age transition. The evidence of this anthropogenic sedimentation event, documented throughout eastern North America, is designated here as pre-colonial sediment (PCS), ca. A.D. 1100–1600. The data demonstrate that the combined effects of prehistoric land use and climate change affected eastern North American floodplain development several hundred years prior to the onset of major European settlement.