While climate is often seen as the main driver of early humans’ spatial organization in Africa, genetic and archaeological studies also suggest diseases as key selective forces in the Pleistocene. We explored whether Plasmodium falciparum –induced malaria drove habitat choice in human societies 74,000 to 5000 years ago. Combining species distribution models of mosquito complexes, palaeoclimatic and epidemiological data, we estimated an index of malaria transmission risk in sub-Saharan Africa through time. We then correlated it with an independent reconstruction of the human niche, demonstrating that humans avoided or were unsuccessful in potential malaria hotspots. Our results highlight the importance of considering disease distributions when modeling past human demography, demonstrating that factors beyond climate underlay population structure, patterns of habitat choice, and dispersal.