As an indicator of climate change, the change of vegetation cover directly reflects the ecosystem dynamics of the region. In this paper, the spatial and temporal characteristics of vegetation cover in the headwaters of the Fen River and the effects of temperature, precipitation, GDP and population on the changes of vegetation cover were statistically analyzed by using the Theil-Sen median slope and the Mann-Kendall test and Pearson’s correlation coefficient from 2000 to 2020. The results showed that: (1) from 2000 to 2020, the vegetation cover of the Fen River headwaters showed an overall upward trend, and the mean value of NDVI was 0.55. The fluctuation increased from 2000 to 2011; the significant increase was observed from 2011 to 2013; and the fluctuation of the value of NDVI from 2013 to 2020 was relatively small p 0.01 . (2) Climate change affects changes in vegetation cover. On the time scale, the 2000-2020 mean NDVI values are positively correlated with temperature and precipitation, but the correlation is not significant p p 0.053 0.05, 0.185 0.05 . On the spatial scale, vegetation cover was weakly negatively correlated with air temperature as a whole, while positively correlated with precipitation as a whole. (3) The influence of human activities on vegetation cover was dominant, NDVI and GDP were positively correlated, with only 5.13% negatively correlated in the central and northeastern part of the region, and NDVI and population were strongly positively and negatively correlated, with alternating distribution in the study area. (4) The vegetation cover of the Fen River headwaters area shows an increasing trend, but there are still ecological and environmental problems, and it is necessary to continue to improve the implementation of the relevant ecological protection policies in order to achieve the goal of sustainable development. The results of the study can provide scientific references for the restoration of vegetation cover and protection of fragile ecosystems in the transition zone of semi-arid and semi-humid climate.