Background Seasonal malaria chemoprevention (SMC) is an effective intervention to prevent malaria in children in locations where the burden of malaria is high and transmission is seasonal. There is growing evidence suggesting that SMC with sulfadoxine-pyrimethamine and amodiaquine can retain its high level of effectiveness in East and Southern Africa despite resistance concerns. This study aims to generate evidence on the effectiveness of SMC when delivered under programmatic conditions in an area with an unknown antimalarial drug resistance profile in the Northern Bahr el-Ghazal region of South Sudan.Methods We conducted a non-randomised quasi experimental study comparing an intervention county with a control county. Five monthly SMC cycles were delivered between July and November 2022, targeting about 19,000 children 3–59 months old. Data were obtained from repeated cross-sectional household surveys of caregivers of children aged 3–59 months using cluster sampling. Wave 1 survey took place in both counties before SMC implementation; Waves 2 and 3 took place after the second and fourth monthly SMC cycles. We performed difference-in-differences analysis by fitting logistic regression models with interactions between county and wave.Results A total of 2,760 children were sampled in the study across the three survey waves in both study counties. Children in the intervention arm had 70% lower odds of caregiver-reported fever relative to those in the control arm during the one-month period prior to Wave 2 (OR: 0.30, 95%CI: 0.12–0.70, p = 0.003), and 47% lower odds in Wave 3 (OR: 0.63, 95%CI: 0.22–1.59, p = 0.306) after controlling for baseline difference between counties in Wave 1. Odds of caregiver-reported RDT-confirmed malaria were 82% lower in the previous one-month period prior to Wave 2 (OR: 0.18, 95%CI: 0.07–0.49, p = 0.001) and Wave 3 (OR: 0.18, 95%CI: 0.06–0.54, p = 0.003).Conclusion These results show high effectiveness of SMC using SPAQ in terms of reducing malaria disease during the high transmission season in children 3–59 month. Despite the promising results, we require the results from the chemoprevention efficacy cohort studies, and analysis of relevant resistance markers, to assess the suitability of SMC for this specific context.