The Missouri River basin is subject to extremes in both high and low flow, with damaging floods and droughts occurring over the instrumental period. Recent events of the 2000s are notable for rapid transitions from dry to wet conditions, and for the different timing of these conditions in the upper and lower basins. This study focuses on drought in the upper and lower Missouri River basins (defined as above and below the Missouri/Yellowstone River confluence), with particular attention to the climate and synoptic scale patterns during drought in the basin's two main source regions over the years 1912–2011. Six drought events were identified in the upper basin, ranging from 2 to 12 years, and eight events were identified in the lower basin, lasting from 2 to 16 years. Almost all upper and lower basin droughts overlapped in time, but only the 1930s drought occurred in both basins over the exact same years. Hydroclimate analyses show that the worst‐case scenario for basin‐wide drought conditions includes a dry winter in the upper basin and a dry spring/summer in the lower basin, accompanied by warm temperatures. The recent 2000s drought in the Missouri River basin displayed anomalous characteristics relative to past droughts, including warm temperatures across the entire basin, particularly in spring and summer, a weakened Great Plains Low Level Jet, and a lag in the upper basin recovery time. In the past, upper basin flows have compounded or ameliorated regional flooding or basin‐wide drought conditions, but a decreasing trend in the upper basin contribution to total Missouri River flow is evident and expected to continue, suggesting its role relative to the lower basin is changing.