The hydrologic data series are nonstationary due to climate change and local anthropogenic activities. The existing nonstationary design flood estimation methods usually focus on the statistical nonstationarity of the flow data series in the catchment, which neglect the hydraulic approach, such as reservoir flood regulation. In this paper, a novel approach to comprehensively consider the driving factors of non-stationarities in design flood estimation is proposed, which involves three main steps: (1) implementation of the candidate predictors with trend tests and change point detection for preliminary analysis; (2) application of the nonstationary flood frequency analysis with the principle of Equivalent Reliability (ER) for design flood volumes; (3) development of a nonstationary most likely regional composition (NS-MLRC) method, and the estimation of a design flood hydrograph at downstream cascade reservoirs. The proposed framework is applied to the cascade reservoirs in the Han River, China. The results imply that: (1) the NS-MLRC method provides a much better explanation for the nonstationary spatial correlation of the flood events in Han River basin, and the multiple nonstationary driving forces can be precisely quantified by the proposed design flood estimation framework; (2) the impacts of climate change and population growth are long-lasting processes with significant risk of flood events compared with stationary distribution conditions; and (3) the swift effects of cascade reservoirs are reflected in design flood hydrographs with lower peaks and lesser volumes. This study can provide a more integrated template for downstream flood risk management under the impact of climate change and human activities.