Water resource carrying capacity (WRCC) is an important index used to measure the sustainable development of a system. Under the background of ecological civilization, research on the spatiotemporal differentiation of regional WRCC and its driving mechanism remains insufficient. The sustainable social and economic development in Yunnan Province still faces water resource challenges for multiple reasons, such as engineering, water shortage, and water pollution. Therefore, based on the analysis of regional water resource endowment and utilization during 2010–2021 in Yunnan Province, this study explores the spatiotemporal variation of regional WRCC and its driving mechanism. First, a comprehensive evaluation index system covering water resources, society, economy, and ecological environment is constructed, with a total of 20 indicators. Then, an improved TOPSIS WRCC evaluation model is constructed based on subjective and objective comprehensive weighting methods. Finally, the geographically and temporally weighted regression (GTWR) model is introduced to examine the driving analysis of WRCC. Results show the following: (1) The WRCC of Yunnan Province depicts an overall increasing trend from the year 2010 to 2021. (2) The WRCC of Yunnan Province has remarkable spatial heterogeneity, and the water resource subsystem is still the major driving force.