SummaryObjectiveTo assess the effectiveness of seasonal malaria chemoprevention (SMC) in reducing under-five malaria morbidity and mortalityDesignUnder-five malaria data for confirmed episodes, deaths, and number of children dosed per cycle of SMC campaign were extracted from the District Health Information Management System (DHIMS-2) for 2018–2019. Data verification was done to compare extracted data with the source for completeness and consistency. Association between SMC and the main outcome variables (malaria cases and mortality) was computed from 2X2 tables and reported as rate ratios at a 95% confidence level.SettingAll seven (7) districts in Savannah Region, GhanaParticipantsChildren under five yearsInterventionSulphadoxine-Pyrimethamine and Amodiaquine (SPAQ) prophylaxis given monthly, four times, durng the rainy season (July to October)Main outcome measuresSMC coverage per cycle and under-five malaria morbidity and mortality ratiosResultsOver 370,000 dose packs of SPAQ were administered with an average cycle coverage of 93%. There was approximately 17% (p<0.01) and 67% (p=0.047) reduction in malaria-related morbidity and mortality, respectively, in the implementation year compared with the baseline. This translated into nearly 9,300 episodes of all forms of malaria and nine malaria-attributable deaths averted by the intervention.ConclusionSMC (combined with existing control measures) wields prospects of accelerating the regional/national malaria elimination efforts if the implementation is optimised. Expansion of the intervention to other high-prevalence regions with seasonal variation in disease burden may be worthwhile.FundingNone declared