The Coupled Model Intercomparison Project Phase 6 (CMIP6) provides more scenarios and reliable climate change results for improving the accuracy of future hydrological parameter change analysis. This study uses five CMIP6 global climate models (GCMs) to drive the variable infiltration capacity (VIC) model, and then simulates the hydrological response of the upper and middle Huaihe River Basin (UMHRB) under future shared socioeconomic pathway scenarios (SSPs). The results show that the five-GCM ensemble improves the simulation accuracy compared to a single model. The climate over the UMHRB likely becomes warmer. The general trend of future precipitation is projected to increase, and the increased rates are higher in spring and winter than in summer and autumn. Changes in annual evapotranspiration are basically consistent with precipitation, but seasonal evapotranspiration shows different changes (0–18%). The average annual runoff will increase in a wavelike manner, and the change patterns of runoff follow that of seasonal precipitation. Changes in soil moisture are not obvious, and the annual soil moisture increases slightly. In the intrayear process, soil moisture decreases slightly in autumn. The research results will enhance a more realistic understanding of the future hydrological response of the UMHRB and assist decision-makers in developing watershed flood risk-management measures and water and soil conservation plans.