The lower Mississippi valley contains multiple large braid belts for which age control has been limited. Application of the optically stimulated luminescence technique has produced a new chronology of lower Mississippi valley channel-belt formation and insight into the valley's evolution during the last glacial cycle. Fluvial deposits range from last interglacial meander belts (85 ± 7 to 83 ± 7 ka) to multiple braid belts (64 ± 5 to 11 ± 1 ka) and record large-amplitude responses of the Mississippi River to glacially induced changes in discharge and sediment supply during the last glacial cycle. Slackwater deposits in buried tributary valleys from the middle Mississippi valley and northern lower Mississippi valley suggest that the river was flowing at a position 8–21 m below the present flood plain during the last interglacial, then rapidly aggraded and switched to a braided regime to form the highest and oldest braid belt by 64 ± 5 to 50 ± 4 ka, coincident with initial glaciation of the upper drainage basin. The Mississippi River remained braided until final meltwater withdrawal from its headwaters in the earliest Holocene. Braid-belt formation and incision was controlled by fluctuations in meltwater and sediment discharge, while glacio-eustatic sea level controlled the elevation to which the river was graded, causing late glacial braid belts to dip below the Holocene flood plain in the southern lower Mississippi valley. Moreover, avulsions in the middle Mississippi valley and northern lower Mississippi valley during the last glaciation have pinned the river over regions of shallow bedrock, preventing the modern river from incising to its last interglacial profile. The new chronology and longitudinal profiles presented here provide insight into the response of this continental-scale river system to climatic (glacial) and base-level forcing during the last 100 k.y. glacial cycle.