Globally, karst regions face the dual challenges of urbanization and ecological protection, with the coupling coordination of multi-dimensional urbanization (MDU) and ecological security (ECS) being a necessary condition for achieving sustainable development. This study, based on statistical data on MDU and ECS in the Yunnan–Guizhou Region (the YGR) in China, employs the entropy weight TOPSIS model, degree of coupling coordination (CCD) model, and panel Tobit regression model to explore the coupling relationship between MDU and ECS. The main conclusions are as follows. (1) MDU in the YGR increased from 0.299 to 0.305, indicating low-level and sluggish development. Spatially, it is characterized by a “dual-core” structure centered on Kunming and Guiyang. (2) ECS decreased from 0.456 to 0.423, with a spatial pattern of “high in the east, low in the west”. The impact of human activities on ECS increased from 0.579 to 0.631 due to the increase in social and economic activities. (3) CCD increased to 0.579, achieving moderate coordination. The spatial feature evolved into a tri-cluster pattern of “high–low–high” across the “eastern–central–northwestern” regions. (4) Regression results indicate that annual average precipitation has a “both promoting and limiting” dual effect on CCD. The coefficient for the proportion of afforested land area is 0.205, with a significance level of 5%, suggesting that increasing forest cover is a key measure for improving CCD. The study reveals the factors influencing the evolution of MDU and ECS from a negative to a positive correlation, providing a basis for decisions related to sustainable development for urban and ecological management in karst landscapes globally.
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