The study on the change of vegetation coverage and its relationship with the driving factors is the basis of benefit evaluation on large-scale vegetation restoration, but the spatial-temporal change patterns of vegetation and its driving factors in the southwest karst trough-valley region are still not clear at present, which is not conducive to further ecological construction. This study explored the spatio-temporal characteristics and driving factors of vegetation coverage change based on the data of NDVI, air temperature, rainfall, DEM, land cover and population density in the southwest trough valley area from 2000 to 2018 and to predict the future trends. The methods of linear trend regression analysis and Hurst index analysis as well as the geographic detector model were applied. The results showed that: (1) In recent 19 years, the range of NDVI was 0.785~0.838, which showed a fluctuating upward trend, and the annual growth rate of vegetation NDVI (0.003 17/a) in karst area was significantly higher than that in non-karst area (0.002 60/a). (2) Hurst index analysis showed that the vegetation NDVI in the study area mainly showed an upward trend, but 64.31% of them would show a degradation trend in the future, and the situation of vegetation protection was more severe. (3) There was a negative correlation between NDVI and temperature change (R=-0.040) in karst area, but a positive correlation (R=0.013) in non-karst area. The results of residual analysis showed that human activities promoted the NDVI growth of 89.60% of regional vegetation. (4) In the whole karst trough-valley area, land cover type and air temperature were the main driving factors affecting NDVI, the interpretation rate was over 25%, and the interaction of each factor was obviously higher than that of a single factor. On the whole, human activities had a significant positive impact on the vegetation restoration in the southwest trough valley area.