Abstract Scientific evaluation of water resources metabolism efficiency (WME) has essential theoretical and practical value for regional water resources security and sustainable utilization. Based on the framework of the water resources metabolism process and construction of the indicator system of WME, the spatiotemporal variations of WME were analyzed using the weighted summation method in the Eastern, Central, and Western regions of China during the period from 1990 to 2020 with heterogeneous resource endowments. The exploratory spatial data analysis (ESDA) and spatial Durbin model were applied to analyze the spatial autocorrelation patterns and reveal spillovers of the WME. The results show that (1) The WME increased at different speeds in the Eastern, Central, and Western regions from 1990 to 2020 with heterogeneous resource endowment, and the spatial variation of WME in the Eastern and Central regions was significantly higher than in the Western regions. (2) The WME had significant spatial autocorrelation except in 2015, indicating obvious spatial agglomeration characteristics and spatial heterogeneity simultaneously. (3) The spatial spillover effects analysis indicated that the waste virtual recycling use ratio, the ratio of output virtual water and input virtual water, and industrial water ratio were the primary factors influencing WME.