Understanding how climate change and cascade dam development jointly influence hydrological extremes is critical for water resources management in large transboundary river basins. This study quantifies the combined effects of reservoir operations and climate change on peak streamflow characteristics in the Mekong River Basin using hydrological modeling and flood-frequency analysis. Streamflow at ten hydrological stations was analyzed considering the influence of 157 existing and planned dams together with climate projections from CMIP6 under four SSP scenarios. Results indicate spatially heterogeneous rainfall patterns, with the highest precipitation in eastern Laos and Vietnam and lower totals in upstream regions. Despite increasing precipitation, peak streamflow at most stations is projected to decline due to reservoir regulation, which attenuates flood peaks and increases dry-season flows. In addition, the timing of annual peak discharge is expected to shift later in the season by approximately 1–1.5 months at downstream stations. Flood frequency analysis shows that the Peaks-Over-Threshold (POT) method consistently produces higher flood estimates than the Annual Maximum Series (AMS), with differences projected to increase in the future due to intensified dam regulation and climate variability. These findings highlight the need for nonstationary flood-frequency approaches that explicitly incorporate reservoir operations and climate change, with important implications for infrastructure design, flood-risk management, and transboundary water governance in the Mekong Basin.