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Characteristics and predictability of drought in the midwestern United States, spanning the from the Great Plains to the Ohio Valley, at local and regional scales are examined during 1916–2015. Given vast differences in hydroclimatic variability across the Midwest, drought is evaluated in four regions identified using a hierarchical clustering algorithm applied to an integrated drought index based on soil moisture, snow water equivalent, and 3-month runoff from land surface models forced by observed analyses. Highlighting the regions containing the Ohio Valley (OV) and Northern Great Plains (NGP), the OV demonstrates a preference for subannual droughts, the timing of which can lead to prevalent dry epochs, while the NGP demonstrates a preference for annual-to-multiannual droughts. Regional drought variations are closely related to precipitation, resulting in a higher likelihood of drought onset or demise during wet seasons: March–November in the NGP and all year in the OV, with a preference for March–May and September–November. Due to the distinct dry season in the NGP, there is a higher likelihood of longer drought persistence, as the NGP is 4 times more likely to experience drought lasting at least one year compared to the OV. While drought variability in all regions and seasons is related to atmospheric wave trains spanning the Pacific–North American sector, longer-lead predictability is limited to the OV in December–February because it is the only region/season related to slow-varying sea surface temperatures consistent with El Niño–Southern Oscillation. The wave trains in all other regions appear to be generated in the atmosphere, highlighting the importance of internal atmospheric variability in shaping Midwest drought. Significance Statement: The midwestern United States, spanning from the Great Plains to the Ohio Valley, has endured many costly and life-altering droughts. A drought in 2012 led to an estimated $34.5 billion in direct economic losses. This study aims to build a more complete understanding of drought in regions of the Midwest that could be used in drought early warning efforts. Drought is evaluated in four midwestern regions of coherent hydroclimatic variability. The regions were identified by applying a method that groups similar objects to an integrated drought index that includes soil moisture, snow water equivalent, and 3-month runoff from land surface models during 1916–2015. Highlighting the regions containing the Ohio Valley (OV) and Northern Great Plains (NGP), droughts in the NGP generally last longer than in the OV. Droughts in the NGP only begin and end during the warm and wet season while droughts in the OV can begin and end during any time of year. El Niño–Southern Oscillation (ENSO), a slow varying phenomenon of the Earth system, may be used as a source of predictability for drought onset and demise in the OV during winter. However, circulation patterns internal to the atmosphere play a key role in shaping drought in all other seasons and regions of the Midwest. [ABSTRACT FROM AUTHOR]