Since the 21st century, China has experienced rapid development, and the spatial and temporal changes in vegetation cover have become increasingly significant. Southern China is a representative region for human activities, climate change, and vegetation change, but the current human understanding of the interactions between vegetation and its influencing factors is still very limited. In our study, we use NDVI as the vegetation greenness data, land cover data, temperature, precipitation, downgradient shortwave radiation, and CO2 data to investigate the interrelationship among vegetation, climate change, and human activities in southern China. The changes and their consistency were studied by trend analysis and Hurst exponent analysis. Then, the contribution of each influencing factor from 2001 to 2020 was quantified by random forest. The results showed that the vegetation in southern China showed an overall rising trend, and areas with a continuous changing trend were concentrated in the Pearl River Delta, western Guangdong, and eastern Guangdong, with a growth rate of 0.02∼0.04%. The vegetation in northern Guangdong did not change significantly. The main factor of NDVI spatial variation in southern China is the land-use factor, accounting for 79.4% of the variation, while climate factors produce further differences. The contributions and lagged effects of NDVI factors on different land-use types and the lagged effects of different climate factors are different and are related to the climate and vegetation background in Sourthern China. Our study is useful in estimating the contribution of NDVI change by each considered factor and formulating environmentally friendly regional development strategies and promoting human–land harmony.