The sustainability of regional water resources has important supporting data needed for establishing policies on the sustainable development of the social economy. The purpose of this paper is to propose an assessment method to accurately reflect the sustainability of regional water resources in various areas. The method is based on the relative entropy of the information entropy theory. The steps are as follows. Firstly, the pretreatment of the evaluation sample data is required, before the relative entropy of each standard evaluation sample and evaluation grade (SEG) is calculated to obtain the entropy weight of each evaluation index. After this, the entropy weighted comprehensive index (WCI) of the standard evaluation grade sample is obtained. The function relation between WCI and SEG can be fitted by the cubic polynomial to construct the evaluation function. Using the above steps, a generalized entropy method (GEM) for the sustainable assessment of regional water resources is established and it is used to evaluate the sustainability of water resources in the Pingba and Huai River areas in China. The results show that the proposed GEM model can accurately reflect the sustainable water resources in the two regions. Compared with the other evaluation models, such as the Shepherd method, Artificial Neural Network and Fuzzy comprehensive evaluation, the GEM model has larger differences in its evaluation results, which are more reasonable. Thus, the proposed GEM model can provide scientific data support for coordinating the relationship between the sustainable development and utilization of regional water resources in order to improve the development of regional population, society and economy.