Understanding the response of vegetation variation to climate change and human activities is critical for addressing future conflicts between humans and the environment, and maintaining ecosystem stability. Here, we aimed to identify the determining factors of vegetation variation and explore the sensitivity of vegetation to temperature (SVT) and the sensitivity of vegetation to precipitation (SVP) in the Shiyang River Basin (SYRB) of China during 2001–2022. The climate data from climatic research unit (CRU), vegetation index data from Moderate Resolution Imaging Spectroradiometer (MODIS), and land use data from Landsat images were used to analyze the spatial-temporal changes in vegetation indices, climate, and land use in the SYRB and its sub-basins (i.e., upstream, midstream, and downstream basins) during 2001–2022. Linear regression analysis and correlation analysis were used to explore the SVT and SVP, revealing the driving factors of vegetation variation. Significant increasing trends (P<0.05) were detected for the enhanced vegetation index (EVI) and normalized difference vegetation index (NDVI) in the SYRB during 2001–2022, with most regions (84%) experiencing significant variation in vegetation, and land use change was determined as the dominant factor of vegetation variation. Non-significant decreasing trends were detected in the SVT and SVP of the SYRB during 2001–2022. There were spatial differences in vegetation variation, SVT, and SVP. Although NDVI and EVI exhibited increasing trends in the upstream, midstream, and downstream basins, the change slope in the downstream basin was lower than those in the upstream and midstream basins, the SVT in the upstream basin was higher than those in the midstream and downstream basins, and the SVP in the downstream basin was lower than those in the upstream and midstream basins. Temperature and precipitation changes controlled vegetation variation in the upstream and midstream basins while human activities (land use change) dominated vegetation variation in the downstream basin. We concluded that there is a spatial heterogeneity in the response of vegetation variation to climate change and human activities across different sub-basins of the SYRB. These findings can enhance our understanding of the relationship among vegetation variation, climate change, and human activities, and provide a reference for addressing future conflicts between humans and the environment in the arid inland river basins.