In Ghana, malaria is endemic and perennial (with significant seasonal variations in the three Northern Regions), accounting for 33 % of all deaths among children under 5 years old, with prevalence rates in children under-five ranging from 11 % in Greater Accra to 40 % in Northern Region. Ghana adopted the WHO-recommended Seasonal Malaria Chemoprevention (SMC) strategy with a trial in the Upper West Region in 2015. The objective of this study was to estimate the cost-effectiveness of seasonal malaria chemoprevention.Costs were analysed from provider and societal perspectives and are reported in 2015 US$. Data on resource use (direct and indirect costs) of the SMC intervention were collected from intervention records and a survey in all districts and at regional level. Additional numbers of malaria cases and deaths averted by the intervention were estimated based on prevalence data obtained from an SMC effectiveness study in the region. Incremental cost-effectiveness ratios (ICERs) were estimated for the districts and region. Sensitivity analyses were conducted to test the robustness of the ICERs.The total financial cost of the intervention was US$1,142,040.80. The total economic cost was estimated to be US$7.96 million and US$2.66 million from the societal and provider perspectives, respectively. The additional numbers of cases estimated to be averted by the intervention were 24,881 and 808, respectively. The economic cost per child dosed was US$67.35 from societal perspective and US$22.53 from the provider perspective. The economic cost per additional case averted was US$107.06 from the provider perspective and US$319.96 from the societal perspective. The economic cost per additional child death averted by the intervention was US$3298.36 from the provider perspective and US$9858.02 from the societal perspective. The financial cost per the SMC intervention delivered to a child under-five was US$9.66. The ICERs were sensitive to mortality rate used.The SMC intervention is economically beneficial in reducing morbidity in children under-5 years and presents a viable approach to improving under-five health in Ghana.