Abstract Potential predictability of 2-yr droughts indicated by low runoff in the consecutive April–September seasons in the upper Missouri River basin (UMRB) and lower Missouri River basin (LMRB) is examined with observed estimates and climate models. The majority of annual runoff is generated in April–September, which is also the main precipitation and evapotranspiration season. Physical features related to low April–September runoff in both UMRB and LMRB include a dry land surface state indicated by low soil moisture, low snowpack indicated by low snow water equivalent, and a wave train across the Pacific–North American region that can be generated internally by the atmosphere or forced by the La Niña phase of El Niño–Southern Oscillation. When present in March, these features increase the risk of low runoff in the following April–September warm seasons. Antecedent low soil moisture significantly increases low runoff risks in each of the following two April–September, as the dry land surfaces decrease runoff efficiency. Initial low snow water equivalent, especially in the Missouri River headwaters of Montana, generates less runoff in the subsequent warm season. La Niña increases the risk of low runoff during the warm seasons by suppressing precipitation via dynamically induced atmospheric circulation anomalies. Model simulations that differ in their radiative forcing suggest that climate change increases the predictability of 2-yr droughts in the Missouri River basin related to La Niña. The relative risk of low runoff in the second April–September following a La Niña event in March is greater in the presence of stronger radiative forcing. Significance Statement Drought spanning consecutive years in the upper Missouri River basin (UMRB) and lower Missouri River basin (LMRB) poses threats to a region whose economy depends on reliable water quantity to support transportation and recreation, adequate water supply for irrigated agriculture, and sufficient streamflow to generate hydroelectric power. We examined physical features in March related to low runoff in the following April–September—low soil moisture, low snow water equivalent, and La Niña events—and examined their effect on the risk of 2-yr drought occurrences. These physical features lead to sustained impacts on the surface water balance. Low snow water equivalent generates less runoff, low soil moisture reduces the runoff efficiency of converting precipitation into runoff, and La Niña inhibits warm-season precipitation and runoff via atmospheric circulation anomalies.