[Objective] The coupling coordination of high-quality development with water resource protection and utilization in Guiyang City, Guizhou Province, were studied in order to provide a scientific basis for further promoting efficient water resource supply and ecological water environment maintenance in southwest karst mountainous areas, thereby promoting regional high-quality development as a whole. [Methods] The research and coordination level, spatial-temporal differentiation characteristics, and factors influencing high-quality development and water resource protection and utilization in Guiyang City from 2010 to 202 were analyzed by using comprehensive evaluation, coupling coordination degree, spatial autocorrelation, and geographic detector models. [Results] The level of high-quality development in Guiyang City has increased significantly over time, while the level of water resource conservation and utilization has fluctuated and decreased. The coupling coordination degree of high-quality development and water resource protection and utilization has shown an increasing trend, and has undergone an evolution process on the verge of malcoordination and barely coordinated areas. The overall spatial distribution pattern was higher in the central and western parts of the city, and lower in the eastern part. The coupling coordination degree had a significant positive spatial correlation, and the spatial correlation between high-high agglomeration and low-high agglomeration was obvious. The influencing factors were highly variable, and the two-factor enhancement effect and non-linear enhancement effect were obvious. [Conclusion] The interdependence between high-quality development and water resource protection and utilization in Guiyang City is increasing, Therefore, in the future, we should enhance the role of innovation as the first driving force, optimize the structure of water resource utilization, improve the capacity to manage “three rivers”, and promote regional coordination and high-quality development.