The current study used the Biome-Bio Geochemical Cycle (Biome-BGC) model to simulate water-use efficiency (WUE) of Piceacrassi folia (P. crassifolia) forest under four representative concentration pathway (RCP) scenarios, and investigated the responses of forest WUE to different combinations of climatic changes and CO2 concentrations in the Qilian Mountains of Northwest China. The model was validated by comparing simulated forest net primary productivity and transpiration under current climatic condition with independent field-measured data. Subsequently, the model was used to predict P. crassi folia forest WUE response to different climatic and CO2 change scenarios. Results showed that (1) increases in temperature, precipitation and atmospheric CO2 concentrations led to associated increases in WUE (ranging from 54% to 66% above the reference climate); (2) effect of CO2 concentration (increased WUE from 36% to 42.3%) was more significant than that of climate change (increased WUE from 2.4% to 15%); and (3) forest WUE response to future global change was more intense at high elevations than at low ones, with CO2 concentration being the main factor that controlled forest WUE variation. These results provide valuable insight to help understand how these forest types might respond to future changes in climate and atmospheric CO2 concentration.