Federal hydropower plants account for approximately half of installed US conventional hydropower capacity, and are an important part of the national renewable energy portfolio. Utilizing the strong linear relationship between the US Geological Survey WaterWatch runoff and annual hydropower generation, a runoff-based assessment approach is introduced in this study to project changes in annual and regional hydropower generation in multiple power marketing areas. Future climate scenarios are developed with a series of global and regional climate models, and the model output is bias-corrected to be consistent with observed data for the recent past. Using this approach, the median decrease in annual generation at federal projects is projected to be less than 2 TWh, with an estimated ensemble uncertainty of ± 9 TWh. Although these estimates are similar to the recently observed variability in annual hydropower generation, and may therefore appear to be manageable, significantly seasonal runoff changes are projected and it may pose significant challenges in water systems with higher limits on reservoir storage and operational flexibility. Future assessments will be improved by incorporating next-generation climate models, by closer examination of extreme events and longer-term change, and by addressing the interactions among hydropower and other water uses.