Catchment runoff is significantly affected by climate condition changes. Predicting the runoff and analyzing its variations under future climates play a vital role in water security, water resource management, and the sustainable development of the catchment. In traditional hydrological modeling, fixed model parameters are usually used to transfer the global climate models (GCMs) to runoff, while the hydrologic model parameters may be time-varying. It is more appropriate to use the time-variant parameter for runoff modeling. This is achieved by incorporating the time-variant parameter approach into a two-parameter water balance model (TWBM) through the construction of time-variant parameter functions based on the identified catchment climate indicators. Using the Ganjiang Basin with an outlet of the Dongbei Hydrological Station as the study area, we developed time-variant parameter scenarios of the TWBM model and selected the best-performed parameter functions to predict future runoff and analyze its variations under the climate model projection of the BCC-CSM1.1(m). To synthetically assess the model performance improvements using the time-variant parameter approach, an index ∆ was developed by combining the Nash-Sutcliffe efficiency, the volume error, the Box-Cox transformed root-mean-square error, and the Kling-Gupta efficiency with equivalent weight. The results show that the TWBM model with time-variant C (evapotranspiration parameter) and SC (water storage capacity of catchment), where growing and non-growing seasons are considered for C, outperformed the model with constant parameters with a ∆ value of approximately 5% and 10% for the calibration and validation periods, respectively. The mean annual values of runoff predictions under the four representative concentration pathways (RCPs) exhibited a decreasing trend over the future three decades (2021-2050) when compared to the runoff simulations in the baseline period , where the values were about −9.9%, −19.5%, −16.6%, and −11.4% for the RCP2.6, RCP4.5, RCP6.0, and RCP8.5, respectively. The decreasing trend of future precipitation exerts impacts on runoff decline. Generally, the mean monthly changes of runoff predictions showed a decreasing trend from January to August for almost all of the RCPs, while an increasing trend existed from September to November, along with fluctuations among different RCPs. This study can provide beneficial references to comprehensively understand the impacts of climate change on runoff prediction and thus improve the regional strategy for future water resource management.