Global warming and anthropogenic changes can result in the heterogeneity of water availability in the spatiotemporal scale, which will further affect the allocation of water resources. A lot of researches have been devoted to examining the responses of water availability to global warming while neglected future anthropogenic changes. What's more, only a few studies have investigated the response of optimal allocation of water resources to the projected climate and anthropogenic changes. In this study, a cascade model chain is developed to evaluate the impacts of projected climate change and human activities on optimal allocation of water resources. Firstly, a large set of global climate models (GCMs) associated with the Daily Bias Correction (DBC) method are employed to project future climate scenarios, while the Cellular Automaton-Markov (CA-Markov) model is used to project future Land Use/Cover Change (LUCC) scenarios. Then the runoff simulation is based on the Soil and Water Assessment Tool (SWAT) hydrological model with necessary inputs under the future conditions. Finally, the optimal water resources allocation model is established based on the evaluation of water supply and water demand. The Han River basin in China was selected as a case study. The results show that: (1) the annual runoff indicates an increasing trend in the future in contrast with the base period, while the ascending rate of the basin under RCP 4.5 is 4.47%; (2) a nonlinear relationship has been identified between the optimal allocation of water resources and water availability, while a linear association exists between the former and water demand; (3) increased water supply are needed in the water donor area, the middle and lower reaches should be supplemented with 4.495 billion m3 water in 2030. This study provides an example of a management template for guiding the allocation of water resources, and improves understandings of the assessments of water availability and demand at a regional or national scale.