Quantitative evaluations on water resources safety in karst areas are of great significance for enacting logical water resources development policies, promoting the sustainability of water resources and realizing sustainable socioeconomic progress. Therefore, according to special characteristics of hydrology and water resources in karst regions of southwestern China, this study constructed an evaluation indicator frame of water resources safety from five aspects: Water resources occurring (WRO), Water environment condition (WEC), “Engineering” water scarcity (EWS), Water resources utilization (WRU) and Water resources management (WRM). Combined weights of assessment indexes were calculated by analytic hierarchy process (AHP) and entropy-right method, and an assessment model of water resources safety in karst regions was constructed based on the coupling of analytical comparison method and alterable vague sets. Taking Guiyang as an example, the water resources safety situation of Guiyang from 2013 to 2022 was assessed with this model and its main obstacle factors were analyzed. Results indicate that the level of water resources safety in Guiyang is on the rise, and the safety level rises from unsafe level to relatively safe level. Water resources utilization is the primary element affecting water resources safety of Guiyang. Total water resources volume, water yielding modulus, consumptive use of water per 10,000 Yuan GDP and exploitation and utilization rate of water resources are primary obstacle factors to the improvement of water resources safety level. The improvement of water resources provision, water resources using efficiency and water resources management all show that human behaviour has a significant impact on water resources safety. The assessment model can impersonally reflect temporal evolution features and main constraints of water resources safety in karst regions, and evaluation results are close to the actual situation, which can provide an effective, feasible and intuitive method for water resources safety evaluation in karst areas.