Selenium (Se) deficiency among populations in Ethiopia is consistent with low concentrations of Se in soil and crops that could be addressed partly by Se-enriched fertilisers. This study examines the disease burden of Se deficiency in Ethiopia and evaluates the cost-effectiveness of Se agronomic biofortification. A disability-adjusted life years (DALY) framework was used, considering goiter, anaemia, and cognitive dysfunction among children and women. The potential efficiency of Se agronomic biofortification was calculated from baseline crop composition and response to Se fertilisers based on an application of 10 g/ha Se fertiliser under optimistic and pessimistic scenarios. The calculated cost per DALY was compared against gross domestic product (GDP; below 1–3 times national GDP) to consider as a cost-effective intervention. The existing national food basket supplies a total of 28·2 µg of Se for adults and 11·3 µg of Se for children, where the risk of inadequate dietary Se reaches 99·1 %–100 %. Cereals account for 61 % of the dietary Se supply. Human Se deficiency contributes to 0·164 million DALYs among children and women. Hence, 52 %, 43 %, and 5 % of the DALYs lost are attributed to anaemia, goiter, and cognitive dysfunction, respectively. Application of Se fertilisers to soils could avert an estimated 21·2–67·1 %, 26·6–67·5 % and 19·9–66·1 % of DALY via maize, teff and wheat at a cost of US$129·6–226·0, US$149·6–209·1 and US$99·3–181·6, respectively. Soil Se fertilisation of cereals could therefore be a cost-effective strategy to help alleviate Se deficiency in Ethiopia, with precedents in Finland.