The lower Ohio River valley is a terraced fluvial landscape that has been profoundly influenced by Quaternary climate change and glaciation. A modern Quaternary chronostratigraphic framework was developed for the lower Ohio River valley using optically stimulated luminescence (OSL) dating and allostratigraphic mapping to gain insights into the nature of fluvial responses to glacial–interglacial/stadial–interstadial transitions and Holocene climate change. River deposits, T0 (youngest) to T7 (oldest), were mapped along a 75 km reach of the lower Ohio River and were dated using 46 OSL and 5 radiocarbon samples. The examination of cores combined with OSL and radiocarbon dating shows that fluvial sediments older than marine oxygen isotope stage (MIS) 2 are present only in the subsurface. Aggradation during MIS 6 (Illinoian glaciation) filled the valley to within ∼7 m of the modern floodplain, and by ∼114 ka (MIS 5e/Sangamon interglacial) the Ohio River had scoured the MIS 6 sediments to ∼22 m below the modern floodplain surface. There were no fluvial sediments in the valley with ages between MIS 5e and the middle of MIS 3. The MIS 3 ages (∼39 ka) and stratigraphic position of T5 deposits suggest the Ohio River aggraded 8–14 m during MIS 4 or MIS 3. Near the end of MIS 3, the Ohio River incised the mid Last Glacial (mid-Wisconsinan) deposits ∼10 m and began aggrading again by ∼30 ka. Aggradation continued into MIS 2, with maximum MIS 2 aggradation occurring before ∼21 ka, which is coincident with the global Last Glacial Maximum (LGM). As the Ohio River adjusted to changing fluxes in sediment load and discharge following the LGM, it formed a sequence of fill-cut terraces in the MIS 2 outwash that get progressively younger with decreasing elevation, ranging in age from ∼21 ka to ∼13 ka. From ∼14 ka to ∼13 ka the Ohio River rapidly incised ∼3 m to form a new terrace, and by ∼12 ka at the onset of the Holocene, the Ohio River established a meandering channel pattern. The river formed a broad floodplain surface from ∼12 ka to ∼6 ka, and then incised ∼1 m and formed a fill-cut terrace from ∼6 ka to ∼5 ka. After ∼5 ka, likely in response to mid-Holocene drought in North America, the Ohio River incised ∼5 m, and by ∼4 ka the river began aggrading again. The Ohio River has aggraded ∼4 m since aggradation began at ∼4 ka. The chronostratigraphic framework and reconstructed history developed here suggest that the lower Ohio River is highly sensitive to glacial–interglacial transitions and abrupt Holocene climate change and responds rapidly to these allogenic forcings.