Understanding the relationship between vegetation and climatic drivers is essential for assessing terrestrial ecosystem patterns and managing future vegetation dynamics. This study examines the effects of local climatic factors and remote large-scale ocean–atmosphere circulations from the Pacific, Atlantic, and Arctic Oceans, as well as the East Asian and Indian summer monsoons, on the spatiotemporal variability of the Normalized Difference Vegetation Index (NDVI) in the karst region of southwest China (KRSC) using Mann-Kendall test, Sen’s slope, cross-correlation, and wavelet analysis. We observed a significant increase in NDVI over karst and non-karst regions from 1981 to 2019, with a notable abrupt shift from 2001 onwards, underscoring the importance of understanding the underlying drivers. The significant correlation and coherence of surface air (TMP) and soil temperatures (ST) with NDVI, especially when analyzed using wavelet methods, indicate their crucial role in vegetation dynamics. Additionally, the broad coherence patterns of AMO and WHWP with NDVI at annual and decadal cycles suggest that ocean–atmosphere interactions also play a significant part. At interannual periodicities, most large-scale indices displayed significant coherence with NDVI. These findings highlight the complexity of NDVI variability, which is better explained by the integration of multiple local and global factors rather than by single variables. The integrated local–global drivers, particularly TMP-ST-AMO-NP-WHWP and PCP-SM-AMO-NP-WHWP with mean coherence of 0.90 and 0.89, respectively, showed the highest mean coherence, emphasizing the need for a multifaceted approach in understanding vegetation changes rather than a single local variable or atmospheric circulation index. These findings have significant implications for policymakers, aiding in better planning and policy formulations considering climate change and atmospheric variability.