We present a reconstruction of human demography and shell fishing activity in the Sine-Saloum mangrove Delta (Senegal) in the past 6000 years using the summed probability density (SPD) of radiocarbon dates in archaeological shell middens. We explore how this local history relates to the climatic and political history of West Africa. We find that traces of human presence were scarce from 6000 to 2000 yr BP, partly because the geomorphology of the estuary was less favorable to human settlements at that time. A specialized shell fishing population migrated massively to the Sine-Saloum around 2000 yr BP, at the end of the aridification trend that followed the African humid period. This population, likely coming from the northern coast in search of land and resources, fleeing from aridity and the subsequent warfare, found refuge in the coastal mangroves and reached a maximum activity at about 1700 yr BP. This period corresponds to the beginning of trans-Saharan trade, and to a political complexification that would give rise to the Ghana empire. The incoming migration may have occurred in two waves as suggested by two peaks in the SPD curve at 200–400 CE and 600–800 CE and by cultural differences within the Delta. Most sites in the Sine-Saloum islands were abandoned in the early 15th century, before the arrival of Europeans, possibly because intensive shell fishing was not sustainable anymore, or because of the regional political destabilization associated to the fall of the Ghana empire and the beginning of the Mali empire. Shortly after, in agreement with oral traditions, a new population lead by the Manding Guelwars, moved to the Sine Saloum after a military defeat and founded the modern towns. They had a reduced shellfishing activity compared to previous inhabitants, possibly because activities were more oriented to the new trade with Europeans or to a prosperous agriculture in more humid climatic conditions that prevailed from 1500 to 1800 CE.