The positions of human activities that request water and the water natural distributions are usually not spatially consistent, which has restricted regional development and sustainability globally. This spatial mismatch emphasizes the urgent need to examine the water resource spatial equilibrium (WRSE). The WRSE is a metric used to overcome the spatial restriction of water resources for regional sustainable development. Although some studies have investigated the WRSE, the implications and the quantitative evaluations have been poorly explained. In line with this background, a novel comprehensive evaluation model for investigating WRSE was developed in this research. In developing this model, the game theory coupling weight method and the coupling coordination degree are jointly adopted to quantify the WRSE performance. The model also includes in-depth investigation, including type classification and accumulative obstacle index analysis, both of which help to identify regions that urgently need to improve their WRSEs and present indicators that have the greatest restriction effects on WRSE. Empirical study performed on 31 provinces in China during 2004–2019 proved the effectiveness of the new comprehensive evaluation model developed in this research for evaluating the WRSE. The demonstration conducted can help decision-makers formulate tailor-made countermeasures on a regional scale to optimize the WRSE, which also proves that the novel comprehensive evaluation model is applicable and effective in evaluating WRSE. This new model not only provides a theoretical reference for conducting WRSE research, but also provides a novel perspective on the sustainable development and utilization of regional water resources.