Inter-annual climatic variability over a large portion of sub-Saharan Africa is under the influence of the El Niño-Southern Oscillation (ENSO). Extreme variability in climate is a threat to rural livelihoods in sub-Saharan Africa, yet the role of ENSO in the balance between supply and demand of net primary productivity (NPP) over this region is unclear. Here, we analyze the impact of ENSO on this balance in a spatially explicit framework using gridded population data from the WorldPop project, satellite-derived data on NPP supply, and statistical data from the United Nations. Our analyses demonstrate that between 2000 and 2013 fluctuations in the supply of NPP associated with moderate ENSO events average ± 2.8 g C m−2 yr.−1 across sub-Saharan drylands. The greatest sensitivity is in arid Southern Africa where a + 1 °C change in the Niño-3.4 sea surface temperature index is associated with a mean change in NPP supply of −6.6 g C m−2 yr.−1. Concurrently, the population-driven trend in NPP demand averages 3.5 g C m−2 yr.−1 over the entire region with densely populated urban areas exhibiting the highest mean demand for NPP. Our findings highlight the importance of accounting for the role ENSO plays in modulating the balance between supply and demand of NPP in sub-Saharan drylands. An important implication of these findings is that increase in NPP demand for socio-economic metabolism must be taken into account within the context of climate-modulated supply.