Global food security in a changing climate depends on both the nutritive value of staple crops as well as their yields. Here, we examined the direct effect of atmospheric CO2 on cassava (Manihot esculenta Cranz., manioc), a staple for 750 million people worldwide. Cassava is poor in nutrients and contains high levels of cyanogenic glycosides that break down to release toxic hydrogen cyanide when damaged. We grew cassava at three concentrations of CO2 (Ca: 360, 550 and 710 ppm) supplied together with nutrient solution containing either 1 mM or 12 mM nitrogen. We found that total plant biomass and tuber yield (number and mass) decreased linearly with increasing Ca. In the worst-case scenario, tuber mass was reduced by an order of magnitude in plants grown at 710 ppm compared with 360 ppm CO2. Photosynthetic parameters were consistent with the whole plant biomass data. It is proposed that since cassava stomata are highly sensitive to other environmental variables, the decrease in assimilation observed here might, in part, be a direct effect of CO2 on stomata. Total N (used here as a proxy for protein content) and cyanogenic glycoside concentrations of the tubers were not significantly different in the plants grown at elevated CO2. By contrast, the concentration of cyanogenic glycosides in the edible leaves nearly doubled in the highest Ca. If leaves continue to be used as a protein supplement, they will need to be more thoroughly processed in the future. With increasing population density, declining soil fertility, expansion into marginal farmland, together with the predicted increase in extreme climatic events, reliance on robust crops such as cassava will increase. The responses to CO2 shown here point to the possibility that there could be severe food shortages in the coming decades unless CO2 emissions are dramatically reduced, or alternative cultivars or crops are developed.