The contradiction between supply and demand of congenital water shortage and acquired water supply in southern Xinjiang stems from the natural accumulation over time and the effects of human long-term production activities on the ecological environment, including its destruction. It is necessary to formulate a scientific and perfect water use plan to improve the contradiction between supply and demand. In order to assess the current state of water supply and demand in southern Xinjiang, a water resource carrying capacity evaluation index system based on the three aspects of water resources, social economy, and ecological environment was constructed using 24 indicators. The spatio-temporal evolution of water resource carrying capacity and coupling coordination between subsystems in southern Xinjiang from 2005 to 2020 was quantitatively evaluated based on the entropy weight-TOPSIS method and coupling coordination model. The results show that: (1) The overall carrying capacity of water resources in southern Xinjiang is low, and the carrying capacity of water resources in Bayingol Mongolian Autonomous Prefecture is good, however, the variation range is wide and the trend is unsteady. The overall carrying capacity of water resources in the Aksu and Kashgar regions showed a fluctuating upward trend, with similar growth rates. Compared with 2005, the comprehensive evaluation value of water carrying capacity in the two regions increased by more than 40% in 2020. The overall water carrying capacity of Kyzylsukol Autonomous Prefecture and the Hotan area showed a fluctuating and decreasing trend first and then slowly rising. The water carrying capacity of resources in the Hotan area fluctuated greatly. (2) From 2005 to 2020, the water-socio-economic-ecological environment in southern Xinjiang was in a low-level coupling stage, indicating that the degree of correlation between various subsystems was poor, and in 2020, the coupling coordination degree transitioned from serious uncoordinated to the basic uncoordinated stage, showing an overall upward trend and large upward space. Among them, Bayingol Mongolian Autonomous Prefecture has the best level of coupling and coordination between subsystems, and the type of mild dysregulation recession has increased from the mild dysregulated recession type to the endangered dysregulated recession type. The coupling coordination level in the other four states increased from the level of moderate imbalance recession to the level of mild imbalance recession. Combined with the comprehensive evaluation values of water resources, socio-economic and ecological environment subsystems, Bayingol Mongol Autonomous Prefecture, Aksu region, and Kashgar region belong to the water resources lagging type. Kyzylsukol Autonomous Prefecture belongs to the socio-economic and ecological environment interaction lag type, and Hotan area belongs to the socio-economic lag type. (3) From the perspective of space, based on geographical differences, the coupling and coordination degree of the five prefectures in southern Xinjiang has a strong correspondence with it. The coupling coordination degree of water resources-socio-economic-ecological environment is better in the east than in the central and western regions. Bayingol Mongolian Autonomous Prefecture has the best level of coupling and coordination, and among the other four regions, Kyzylsukol Autonomous Prefecture has a slow increase in coupling and coordination due to its western border and complex geographical environment, while Aksu, Kashgar, and Hotan regions have similar change rates and stable growth trends.