The origin and significance of pimple mounds (low, elliptical to circular dune-like features found across much of the south-central United States) have been debated for nearly two centuries. We cored pimple mounds at four sites spanning the Ozark Plateau, Arkansas River Valley, and Gulf of Mexico Coastal Plain and found that these mounds have a regionally consistent textural asymmetry such that there is a significant excess of coarse-grained sediment within their northwest flanks. We interpret this asymmetry as evidence of an eolian depositional origin of these mounds and conclude they are relict nebkhas (coppice dunes) deposited during protracted middle to late Holocene droughts. These four mounds yield optically stimulated luminescence ages between 2400 and 700 yr that correlate with well-documented periods of eolian activity and droughts on the southern Great Plains, including the Medieval Climate Anomaly. We conclude vegetation loss during extended droughts led to local eolian deflation and pimple mound deposition. These mounds reflect landscape response to multi-decadal droughts for the south-central U.S. The spatial extent of pimple mounds across this region further underscores the severity and duration of late Holocene droughts, which were significantly greater than historic droughts.