The Lower Mississippi Valley provides an exceptional field example for studying the response of a continental-scale alluvial system to upstream and downstream forcing associated with the large, orbitally controlled glacial-interglacial cycles of the late Quaternary. However, the lack of a numerical chronology for the widespread Pleistocene strata assemblage known as the Prairie Complex, which borders the Holocene floodplain of the Lower Mississippi River, has so far precluded such an analysis. Here, we apply optically stimulated luminescence (OSL) dating, mainly on silt-sized quartz from Prairie Complex strata. In total, 27 OSL ages indicate that the Prairie Complex consists of multiple allostratigraphic units that formed mainly during marine isotope stages 7, 5e, and 5a. Thus, the aggradation of the Prairie Complex is strongly correlated with the sea-level highstands of the last two glacial-interglacial cycles. Fluvial incision during the sea-level fall associated with the MIS 5a–MIS 4 transition extended as far inland as ∼600 km from the present-day shoreline, testifying to the dominant downstream control of fluvial stratigraphic architecture in the Lower Mississippi Valley. In addition, the short reaction time of the Lower Mississippi River suggests that large fluvial systems can respond much more rapidly to allogenic forcing than is commonly believed.