The glacier is a crucial freshwater resource in arid and semiarid regions, and the vulnerability of the glacier change is intimately linked to regional ecological services and socio-economic sustainability. Taking the Tianshan Mountains region in China as an example, a basic framework for studying the vulnerability of glacier change was constructed so as to address factors such as physical geography, population status, socio-economic level, agricultural development, and social services. The framework was based on key dimensions, that is, exposure, sensitivity, and adaptability, and this constituted a targeted evaluation index system. We examined the spatial structure and spatial autocorrelation of the glacier change vulnerability using ArcGIS and GeoDa software. The influence and interaction of natural, social, economic, population and other factors on glacier change adaptability was examined using the GeoDetector model. The results suggested the following: (1) The vulnerability level decreased from the western region to the eastern region with significant differences between the two regions. The eastern region had the lowest vulnerability, followed by the central region, and then western region which had the highest vulnerability. (2) Significant positive and negative correlations were found between exposure, sensitivity, and adaptability, indicating that the areas with high exposure and high sensitivity to glacier change tended to have a low adaptive capacity, which led to high vulnerability, and vice versa. (3) The spatial heterogeneity regarding the ability to cope with glacier change reflected the combined effects of the natural, social, economic, and demographic factors. Among them, factors such as the production value of secondary and tertiary industries, the urban population, urban fixed-asset investment, and the number of employees played major roles regarding the spatial heterogeneity of glacier change.