The topography and geomorphology of southwest China are complex, and the intensity of human activities not balanced. The impact of climate change and anthropogenic activities on vegetation shows temporal and spatial differences. Therefore, we used normalized difference vegetation index (NDVI) to analyze the impact of climate change and anthropogenic activities on vegetation in four provinces and municipality in the southwest China from 2000 to 2015. The results showed that (1) NDVI increased 0.004-0.005/yr during this period. About 57.7496-69.09% of the area with significant changes was found to be primarily affected by anthropogenic activities during all four seasons and the growing season, while 6.05%-10.74% and 5.099-9.77% of the area was affected by temperature and precipitation, respectively. (2) The impact of temperature and precipitation changes were spatially heterogeneous. Temperature had a positive impact during spring and summer in the northwestern region. Furthermore, NDVI was positively affected in the southwestern and eastern regions, while the western region was negatively affected by precipitation. Summer temperatures and precipitation had the greatest impact throughout the year. (3) Returning farmland to forests and improving agricultural management demonstrated positive impacts of anthropogenic activities on the vegetation, while areas with significant negative impacts due to anthropogenic activities were located near the provincial capitals of the four provinces and municipality. This study can provide a scientific basis for accurately identifying key ecological protection areas in Southwest China.