Based on the NDVI and climate data from 2000 to 2022, this study systematically investigated the spatial and temporal patterns, trend characteristics, and stability of the NDVI in Xinjiang using the one-way linear regression method, Theil–Sen Median trend analysis, the Mann–Kendall significance test, and the coefficient of variation. Meanwhile, the persistence of the NDVI distribution was analyzed by combining the trend results and Hurst index. Finally, partial correlation analysis was used to deeply explore the response mechanisms of interannual and seasonal-scale NDVI and climatic factors in Xinjiang, and the characteristics of multi-year vegetation distribution were comprehensively analyzed with the help of human footprint data. The findings indicate the following: (1) The NDVI of interannual and seasonal vegetation in Xinjiang showed a significant increasing trend during the 23-year period, but the spatial distribution was heterogeneous, and the improvement of the vegetation condition in the southern part of the region was remarkable. (2) The NDVI is relatively stable across the region. Unlike in other regions, in general, it is difficult to maintain the existing trend in NDVI in the study area for a long period of time, and the reverse trend is more persistent. (3) On the interannual scale, both precipitation and temperature are positively correlated with the NDVI, and the influence of temperature (80.94%) is greater than that of precipitation (63.82%). Precipitation was dominantly positively correlated with the NDVI in spring, summer, and the growing season, while it was negatively correlated with it in autumn. Temperature and NDVI were positively correlated, with the greatest influence in the spring. (4) Human activities had the greatest impact on the areas with low vegetation cover and areas with medium–low vegetation cover, and there was a high degree of overlap between the areas where the interannual human footprints and NDVI showed an increasing trend. The percentage of human footprints that significantly correlated with interannual NDVI was 34.79%. In the future, the protection and management of ecologically fragile areas should be increased to increase desert-vegetation cover.