Vegetation dynamics plays a critical role in causing the decadal variability of precipitation over the Sahel region of West Africa. However, the potential impact of changes in CO2 concentration on vegetation dynamics and precipitation variability of this region has not been addressed by previous studies. In this paper, we explore the role of CO2 concentration in the regional climate system of West Africa using a zonally symmetric, synchronously coupled biosphere-atmosphere model. We first document the response of precipitation and vegetation to incremental changes of CO2 concentration; the impact of CO2 concentration on the variability of the regional biosphere-atmosphere system is then addressed using the second half of the twentieth century as an example. An increase of CO2 concentration causes the regional biosphere-atmosphere system to become wetter and greener, with the radiative effect of CO2 and improved plant-water relation dominant in the Sahelian grassland region and the direct enhancement of leaf carbon assimilation dominant in the tree-covered region to the south. Driven by the observed sea surface temperature (SST) of the tropical Atlantic Ocean during the period 1950–97 and with CO2 concentration prescribed at a pre-industrial level 300ppmv, the model simulates a persistent Sahel drought during the period of 1960s−1990s. The simulated drought takes place in the form of a transition of the coupled biosphere-atmosphere system from a wet/green regime in the 1950s to a dry/barren regime after the 1960s. This climate transition is triggered by SST forcing and materialized through vegetation-climate interactions. The same SST forcing does not produce such a persistent drought when a constant modern CO2 concentration of 350ppmv is specified, indicating that the biosphere-atmosphere system at higher CO2 level is more resilient to drought-inducing external forcings. This finding suggests that the regional climate in Sahel, which tends to alternate between dry and wet spells, may experience longer (or more frequent) wet episodes and shorter (or less frequent) dry episodes in the future than in the past. Our study has significant implications regarding the impact of climate change on regional socio-economic development.