The response of continental-scale drainage systems to short-term (i.e., millennial-scale) climate change is unknown but has wide implications for understanding climate feedbacks and terrestrial-marine fluxes. The late Wisconsin Mississippi River to deep-sea fan of North America was one of Earth’s largest sediment-routing networks during the most recent glacio-eustatic cycle. To understand late Pleistocene sediment production and dispersal related to the partly glaciated, ancestral Mississippi system, we sampled late Wisconsin deep-sea fan channel-fill and lobe deposits for detrital zircon U-Pb and (U-Th)/He double-dating analyses, from Deep Sea Drilling Project (Leg 96) cores and U.S. Geological Survey piston cores. Our results suggest a late Pleistocene glacial Mississippi system that forced a larger transfer of sediment from Cordilleran magmatic provinces and the Canadian Shield when compared to the modern drainage. This indicates a potentially more expansive and/or erosive ancestral Mississippi catchment, and the efficient dispersal of terrigenous sediment, nutrients, and solutes into the deep-sea via high-discharge meltwater and glacial-lake outbursts during ice retreat.