Learning whether the discharge of large amounts of liquor production wastewater in China affects water quality is crucial to maintaining sustainable economic development, especially in the vulnerable eco-environment of the karst area. The present study investigated the relationship between liquor production wastewater and water quality in the Chishui River Basin for the first time and proposes several constructive suggestions. After river remediation, water quality in spring, summer, autumn, and winter in the Chishui River Basin was found to be at an excellent level, with water quality in winter being the best. Worse water quality and higher health risks were found in liquor production areas (Guling County and Renhuai City) in comparison with other areas. The developed structural equation model showed that physicochemical indexes (especially in N and P) have a higher influence on water quality in comparison with the algae community, heavy metals, and environmental factors. Because liquor being a pillar industry in the locality and these factories discharging an enormous amount of wastewater every year, our results show that liquor production wastewater have affected the water quality to some extent in the Guling County and Renhuai City sections of the Chishui River Basin, and fortunately, the health risks were acceptable in 2020. To prevent potential risks, we suggest that a related department should apply a stricter standard to wastewater discharge. Furthermore, law-enforcement departments can encourage enterprises to develop or introduce more advanced water treatment technologies to achieve as much pollutionfree discharge as possible. Our other suggestion is to develop a project to cleanly produce mineral water in highquality water-resource areas along the Chishui River Basin, contributing to the sustainable growth of the shoreside economy.