Vegetation is known to be sensitive to both climate change and anthropogenic disturbance in the karst region. However, the relationship between an abrupt change in vegetation and its driving factors is unclear at multiple timescales. Based on the non-parametric Mann-Kendall test and the ensemble empirical mode decomposition (EEMD) method, the abrupt changes in vegetation and its possible relationships with the driving factors in the karst region of southwest China during 1982–2015 are revealed at multiple timescales. The results showed that: (1) the Normalized Difference Vegetation Index (NDVI) showed an overall increasing trend and had an abrupt change in 2001. After the abrupt change, the greening trend of the NDVI in the east and the browning trend in the west, both changed from insignificant to significant. (2) After the abrupt change, at the 2.5-year time scale, the correlation between the NDVI and temperature changed from insignificantly negative to significantly negative in the west. Over the long-term trend, it changed from significantly negative to significantly positive in the east, but changed from significantly positive to significantly negative in the west. The abrupt change primarily occurred on the long-term trend. (3) After the abrupt change, 1143.32 km2 farmland was converted to forests in the east, and the forest area had significantly increased. (4) At the 2.5-year time scale, the abrupt change in the relationships between the NDVI and climate factors was primarily driven by climate change in the west, especially rising temperatures. Over the long-term trend, it was caused by ecological protection projects in the east, but by rising temperatures in the west. The integration of the abrupt change analysis and multiple timescale analysis help assess the relationship of vegetation changes with climate changes and human activities accurately and comprehensively, and deepen our understanding of the driving mechanism of vegetation changes, which will further provide scientific references for the protection of fragile ecosystems in the karst region.