The water resources in the arid region of northwestern China, which are impacted by climate change, tend to be more unstable, and the environment and ecosystems will suffer from severe water shortage. In this paper, potential future climate trends were predicted based on CMIP5 simulations in this region. The water availability and agricultural water demand under future climate change scenarios were estimated. Impacted by increases in temperature, the irrigation water demand will increase by 4.27–6.15 billion m3 in this region over the next 60 years, compared to the demand of 32.75 billion m3 during 1971–2000. However, the annual runoff will only increase by 4.8–8.5 billion m3, which is equivalent to or even less than the increased irrigation water demand. In fact, the increased demand for industrial, domestic and ecological water were not considered here. Thus, the water supply/demand contradiction will result in more severe water shortages in the future. According to a comparison with simulated irrigation water demand under three adaptation strategy scenarios, we should take effective measures such as improving the efficiency of irrigation water utilization, reducing crop planting areas and adjusting crop planting structures to alleviate the impacts of future climate changes and human activities on the water supply and water use in this region.