The Three-River Headwaters Region (TRHR) is an area of crucial significance for the ecological security of China. Owing to dramatic climate change and human activities driven by a series of ecological restoration projects, the ecological environment and vegetation have changed drastically in recent years. However, our knowledge of the current state and driving force of the change in the entire region is limited. This study mapped the spatiotemporal changes in vegetation coverage and quantitatively identified the contributions of climate change and anthropogenic factors to such variations from 2000 to 2018 using 133 MODIS NDVI images at 250 m resolution. The results show that over the past 19 years, the average NDVI demonstrated a fluctuating but upward trend, with a rate of increase of 0.0013 yr⁻¹. Areas with increased vegetation coverage accounted for 54.93% of the entire area, and among them, 18.52% showed a significant greening trend. Based on the Hurst exponent, areas with sustained increasing trends were primarily concentrated in the northeastern, western, and southwestern parts of the Yellow River region, and the western Yangtze River region. The average contributions of the precipitation, temperature, and sunshine duration to NDVI were 0.069, 0.098, and 0.059%·yr⁻¹, respectively. Sunshine duration had the greatest influence on the inter-annual change of NDVI during the entire study period, while the temperature was the main climatic factor from 2000 to 2010. The average contributions of climate change and anthropogenic factors to inter-annual variations of NDVI were 0.226 and –0.096%·yr⁻¹, respectively. The general climate conditions are beneficial to the vegetation recovery, whereas human activities negatively impact the vegetation growth. However, the ecological afforestation projects positively influenced the east Yellow River, Lancang River, and west Yangtze River regions.