Water use efficiency (WUE) is critical for conserving water resources and protecting the environment, yet the lack of quantitative analysis of its spatial spillover effects and the spatial heterogeneity of its influencing factors hinders improving and achieving the spatial equilibrium regulation of regional WUE. In the current study, a way is proposed to explore the spatial pattern and driving forces of regional WUE from spatial spillover and heterogeneity perspective, in which the Improved Super‐slack‐based Model is firstly applied to estimate the WUE, and then, the spatial Markov chain and the geographically and temporally weighted regression model were, respectively, used to explore the spatial spillover effects of WUE and reveal the spatial heterogeneity of the driving forces behind the WUE. Guangdong Province, a region with rapidly developing economy and significant uneven development in China, was chosen as a case study. Results show that there is a radial pattern of high WUE in the Pearl River Delta and there are significant spatial spillover effects among cities, the city with higher WUE exerted positive effects on its neighboring city's WUE. The key driving factors of WUE include per capita GDP, per capita water consumption, proportion of secondary and tertiary industry water use, foreign direct investment, and R&D input, with spatial heterogeneity in their influences. Policies such as enhancing public awareness of water saving, increasing the reuse of wastewater in industrial parks, and promoting the inter‐municipal socioeconomic and technological exchanges are recommended to achieve a more coordinated and balanced regional WUE. The results of this study have scientific and practical implications for coordinating regional water resources exploitation and sustainable development.