The Hanjiang River Basin (HJRB) is an important water conservation and ecological barrier area for the South–North Water Transfer Central Project. The quantitative analysis of regional differences in vegetation changes and their main drivers is important for the monitoring of the ecological environment of the basin and formulation of ecological protection measures. Based on MODIS13Q1 data from 2000 to 2020, spatiotemporal variation characteristics of vegetation in the HJRB were analyzed using Theil–Sen + Mann–Kendall, the Hurst index, and correlation analysis. Then, we detected the drivers using an optimal parameter geographic detector. The results showed that from 2000 to 2020, the average NDVI value increased from 0.651 to 0.737, with a spatial distribution pattern of “high in the northwest and low in the southeast”, and 88.68% of the study area showed an increase in vegetation cover, while 5.80% showed a significant degradation. The positive persistence of future vegetation changes is stronger than the negative. It may show a slowdown or degradation trend, among which the vegetation restoration along the Han River and urbanized areas need to be strengthened. The factor detector indicated that the main factors influencing vegetation change were topography and climate, for which the most influential variables, respectively, were elevation (0.1979), landform (0.1720), slope (0.1647), and soil type (0.1094), with weaker influence from human activity factors. The interaction test results showed that the interaction of various geographic factors enhanced the explanatory power of vegetation changes and showed mainly nonlinear and two-factor enhancements. The dominant factor varies between sub-basins; for example, the interaction between wind speed and land use conversion was the dominant factor in the middle reaches of the HJRB; the dominant factor in the lower reaches of the HJRB was expressed as the interaction between land use conversion and temperature. Finally, the effects of the range or category of different drivers on vegetation growth were systematically analyzed. The results of the study contribute to the understanding of the dynamic changes of vegetation based on a comprehensive consideration of the interaction of topography, climate, and human activities, taking into account the totality and variability of the geographical environment, and provide a reference for the ecological restoration and rational use of vegetation resources in the HJRB.