Relative impacts of multiple global change factors on ecohydrological processes in terrestrial ecosystems have not been carefully studied. In this study, we used a terrestrial ecosystem (TECO) model to examine effects of three global change factors (i.e., climate warming, elevated CO2, and altered precipitation) individually and in combination on runoff, evaporation, transpiration, rooting zone soil moisture content, water use efficiency (WUE), and rain use efficiency (RUE) in a North American tallgrass prairie. We conducted a total of 200 different scenarios with gradual changes of the three factors for 100 years. Our modeling results show strong responses of runoff, evaporation, transpiration, and rooting zone soil moisture to changes in temperature and precipitation, while effects of CO2 changes were relatively minor. For example, runoff decreased by 50% with a 10°C increase in temperature and increased by 250% with doubled precipitation. Ecosystem-level RUE increased with CO2, decreased with precipitation, and optimized at 4–6°C of warming. In contrast, plant-level WUE was highest at doubled CO2, doubled precipitation, and ambient temperature. The different response patterns of RUE and WUE signify that processes at different scales responded uniquely to climate change. Combinations of temperature, CO2, and precipitation anomalies interactively affected response magnitude and/or patterns of ecohydrological processes. Our results suggest that ecohydrological processes were considerably affected by global change factors and then likely regulate other ecosystem processes, such as carbon and nitrogen cycling. In particular, substantial changes in runoff to different climate change scenarios could have policy implications because it is a major component to replenishing freshwater. These modeling results should be tested by and could influence design of field experiments on ecohydrological processes.