The Aksu River Basin in the arid southern Xinjiang of China has a fragile ecosystem. Groundwater is one of the key factors restricting the growth and development of surface vegetation in arid areas. Quantitatively analyzing the relationship between groundwater depth affected by natural and anthropogenic factors and vegetation coverage is crucial for ecosystem security. This study selects the MOD13Q1 data and the groundwater depth data during the vegetation growing season (from May to September) from 2015 to 2020. Through linear analysis and the Geodetector model (GDM), this study quantitatively analyzed the response relationships among vegetation cover, land desertification, and groundwater depth. Using the GDM, it quantified the influence of 12 driving factors on the NDVI (Normalized Difference Vegetation Index). Additionally, it clarified the driving force behind the vegetation NDVI and its key factors, as well as the optimal range and type of factors conducive to vegetation growth, providing references and bases for ecological protection and sustainable development. Our study has demonstrated that: (1) Vegetation NDVI was most sensitive to groundwater depths of 2 similar to 8 m. (2) Groundwater depths < 5 m increased vegetation cover, while depths > 8 m led to stable desertification levels. (3) The main factors affecting NDVI were land use type, soil moisture, and groundwater depth. (4) Factor interactions were primarily nonlinear, with land use and soil moisture having the strongest interaction. The optimal groundwater depth range for vegetation growth was 2.3 similar to 4.2 m.