Objective: To assess the effectiveness of seasonal malaria chemoprevention (SMC) in reducing under-five malaria morbidity and mortalityDesign: Under-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 be-tween 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.Setting: All seven (7) districts in Savannah Region, GhanaParticipants: Children under five yearsIntervention: Sulphadoxine-Pyrimethamine and Amodiaquine (SPAQ) prophylaxis given monthly, four times, during the rainy season (July to October)Main outcome measures: SMC coverage per cycle and under-five malaria morbidity and mortality ratiosResults: Over 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.Conclusion: SMC (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.