Regional change in the variability and magnitude of flooding could be a major consequence of future global climate change. Extreme floods have the capacity to rapidly transform landscapes and expose landscape vulnerabilities through highly variable spatial patterns of inundation, erosion, and deposition. We use the historic activation of the Birds Point-New Madrid Floodway during the Mississippi and Ohio River Flooding of 2011 as a scientifically unique stress experiment to analyze indicators of floodplain vulnerability. We use pre- and postflood airborne Light Detection and Ranging data sets to locate erosional and depositional hotspots over the 540 km² agricultural Floodway. While riparian vegetation between the river and the main levee breach likely prevented widespread deposition, localized scour and deposition occurred near the levee breaches. Eroded gullies nearly 1 km in length were observed at a low ridge of a relict meander scar of the Mississippi River. Our flow modeling and spatial mapping analysis attributes this vulnerability to a combination of erodible soils, flow acceleration associated with legacy fluvial landforms, and a lack of woody vegetation to anchor soil and enhance flow resistance. Results from this study could guide future mitigation and adaptation measures in cases of extreme flooding.