In the past few decades, the water resources in the Tang–Bai River Basin showed a declining trend, due to the human–driven alteration of surface water and groundwater management. There are potential risks to the sustainable utilization of future water resources in response to agricultural, industrial, and domestic water supply. In this work, we used the water allocation and regulation model based on SWAT (SWAT–WARM model) to quantify the characteristics of water resources response under human activities in this basin. The multi–source water supply module was modified to improve the applicability of the SWAT–WARM model in this basin. We validated our simulations against observed runoff, water consumption, and supply. The main results were as follows: (a) We used the percent bias, the correlation coefficient, and the Nash–Sutcliffe efficiency coefficient to measure the model validity and found that the modified model did not show obvious advantages in runoff simulations, whereas it reproduced water consumption and supply better than the original model. The modified model had more advantages in reflecting the process of water resources transformation and utilization in the basin driven by strong human activities. (b) By comparing the variation of watershed water circulation fluxes under natural and human disturbance conditions in the Tang–Bai River Basin from 1995 to 2016, we found that human activities increased evapotranspiration by 6.8% and surface runoff increased by 10.0%, while groundwater resources decreased by 0.23 million m3/yr. (c) There was water shortage in the basin at different flow frequencies, among which agricultural water shortage accounted for the largest proportion, >70%. The basin should further strengthen agricultural and industrial water saving, reduce water consumption fundamentally, and ensure the sustainable development of economy and society.