Introduction: The vegetation dynamics of the Sahel-Sudan-Guinea region in Africa, one of the largest transition zones between arid and humid zones, is of great significance for understanding regional ecosystem changes. However, a time-unvarying trend based on linear assumption challenges the overall understanding of vegetation greenness evolution and of tracking a complex ecosystem response to climate in the Sahel-Sudan-Guinea region. Methods: This study first applied the ensemble empirical mode decomposition (EEMD) method to detect the time-varying trends in vegetation greenness based on normalized difference vegetation index (NDVI) data in the region during 2001–2020, and then identified the dominant climatic drivers of NDVI trends by employing explainable machine learning framework. Results: The study revealed an overall vegetation greening but a significant nonlinear spatio-temporal evolution characteristic over the region. Trend reversals, i.e., browning-to-greening and greening-to-browning, were dominant in approximately 60% of the study area. The browning-to-greening reversal was primarily observed in the southern Sahel, Congo Basin north of the Equator, and East Africa, with a breakpoint around 2008, while the greening-to-browning reversal was mainly observed in West Africa, with a breakpoint around 2011. The sustained greening primarily took place in northern Sahel, Central African Republic and South Sudan; while sustained browning clustered in central West Africa and Uganda, mainly in agricultural lands. Furthermore, the combination of Random Forest (RF) algorithm and the SHapley Additive exPlanations (SHAP) method could robustly model and reveal the relationships between the observed trends in NDVI and in climatic variables, also detected by applying EEMD. The results suggested that air temperature and precipitation were the most important climatic drivers controlling the NDVI trends across the Sahel-Sudan-Guinea region. The NDVI trends were more likely to have negative correlations with solar radiation and vapor pressure deficit in arid areas, while they could have positive correlations in humid areas. The study also found that large-scale climate changes induced by sea surface temperature (SST) anomalies had strong relationships with trend reversals in vegetation greenness at a sub-continental scale. These findings advanced the understanding of the impacts of climatic drivers on vegetation greenness evolution in the Sahel-Sudan-Guinea region.