[Objective] The response of vegetation coverage to climate change and human activities in Guizhou Province was studied to provide important guidance for restoring the regional ecological environment.[Methods] Based on MODIS13 A1 data and meteorological data, the spatio-temporal variation in the normalized difference vegetation index (NDVI) during 2001-2018 in Guizhou Province was analyzed. Moreover, the impact of climate change and human activities on the NDVI was explored with linear trend analysis, partial correlation, and residual methods.[Results] ① The NDVI showed a significant upward trend at a growth rate of 0.005 3 per year in Guizhou Province during 2001-2018. In the space studied, the extremely significant and the significant improvement areas accounted for 52.80% and 16.80% of the study area, respectively. ② The climate showed a process of distinct warming and increasing humidity in Guizhou Province during 2001-2018. The NDVI was positively correlated with temperature and precipitation, and the NDVI was more sensitive to temperature than to precipitation. ③ There was no lag in the response of NDVI changes to temperature on a monthly scale, but there was a one-month lag in the response to precipitation. The correlation between the NDVI and climate change on a monthly scale was higher than that on an annual scale. ④ The effect of human activities on vegetation coverage was increasing in Guizhou Province, and the contribution to the NDVI was 72.30%.[Conclusion] The impact of human activities on the NDVI was greater than that of climate change. The spatio-temporal variation in the NDVI was the result of the combined effects of climate change and human activities in Guizhou Province.