The potential drivers of vegetation changes in the Sudano-Sahelian region of Africa remain poorly understood due to complex interactions between climatic and anthropogenic processes. In this study, we analyzed the vegetation greenness trends in relation to rainfall variability that we considered the essence of climatic effects on vegetation in a well-known water-limited environment by using time series of satellite data in the Sudano-Sahelian region during 2001–2020. We quantified in more detail the relative contributions of rainfall variability (climatic factor), land use/land cover (LULC) change, and fire occurrence change (non-climatic factors) to vegetation greenness trends in selected sub-regions. The results showed that vegetation greening was widespread (26.9% of the total study area), while vegetation browning was more clustered in central West Africa (5% of the total study area). About half of the vegetation greening area can be explained by long-term rainfall variability during 2001–2020, but most of the area characterized by a browning trend was unrelated to rainfall variability. An analysis of the relative importance showed that LULC changes had significant local effects on vegetation greenness and that these changes were characterized by a strong spatial heterogeneity in specific sub-regions. Gains in cropland and natural vegetation related to positive land management were probably the dominant drivers of greening in Senegal and Ethiopia. Also, the combined impacts of rainfall variability and LULC changes contributed to greening trends in the arid zone, particularly in Mali and Sudan. In contrast, vegetation browning in central West Africa appeared to be driven by cropland gain and natural vegetation loss associated with extensive agricultural production activities. Furthermore, we found that repeated fires for agricultural expansion in central West Africa intensified vegetation browning. These results advanced our understanding of vegetation dynamics in response to climatic and non-climatic factors in Sudano-Sahelian drylands characterized by increasing pressures on land resources.