The three-river headwater region (TRHR) supplies the Yangtze, Yellow, and Lantsang rivers, and its ecological environment is fragile, hence it is important to study the surface vegetation cover status of the TRHR to facilitate its ecological conservation. The normalized difference vegetation index (NDVI) can reflect the cover status of surface vegetation. The aims of this study are to quantify the spatial heterogeneity of the NDVI, identify the main driving factors influencing the NDVI, and explore the interaction between these factors. To this end, we used the global inventory modeling and mapping studies (GIMMS)-NDVI data from the TRHR from 1982 to 2015 and included eight natural factors (namely slope, aspect, elevation, soil type, vegetation type, landform type, annual mean temperature, and annual precipitation) and three anthropogenic factors (gross domestic product (GDP), population density, and land use type), which we subjected to linear regression analysis, the Mann-Kendall statistical test, and moving t-test to analyze the spatial and temporal variability of the NDVI in the TRHR over 34 years, using a geographical detector model. Our results showed that the NDVI distribution of the TRHR was high in the southeast and low in the northwest. The change pattern exhibited an increasing trend in the west and north and a decreasing trend in the center and south; overall, the mean NDVI value from 1982 to 2015 has increased. Annual precipitation was the most important factor influencing the NDVI changes in the TRHR, and factors, such as annual mean temperature, vegetation type, and elevation, also explained the vegetation coverage status well. The influence of natural factors was generally stronger than that of anthropogenic factors. The NDVI factors had a synergistic effect, exhibiting mutual enhancement and nonlinear enhancement relationships. The results of this study provide insights into the ecological conservation of the TRHR and the ecological security and development of the middle and lower reaches.