BackgroundSeasonal malaria chemoprevention (SMC) is one of the main interventions recommended by WHO to prevent and reduce childhood malaria. Since 2015, Guinea has implemented SMC targeting children aged 3–59 months (CU5) in districts with high and seasonal malaria transmission.ObjectiveWe assessed the programmatic impact of SMC in Guinea’s context of scaled-up malaria intervention programming by comparing malaria-related outcomes in 14 districts that had (n = 8) or had not (n = 6) been targeted for SMC.MethodUsing routine health management information system data, we calculated the district-level monthly test positivity rate (TPR) and monthly uncomplicated and severe malaria incidence for the whole population and disaggregated age groups (<5yrs and ≥5yrs of age). Changes in malaria indicators through time were analyzed by calculating the district-level compound annual growth rate (CAGR) from 2014 to 2021; we used statistical analyses to describe the time trend of the number of tested clinical cases, TPR, uncomplicated malaria incidence, and severe malaria incidence.ResultThe CAGR of TPR of all age groups was statistically lower in SMC (median = −7.8%, range [IQR] = −9.7%, −5.5%) compared to non-SMC (median = −3.0%, IQR = −3.0%, −1.2%) districts. Similarly, the CAGR in uncomplicated malaria incidence was significantly lower in SMC (median = 1.8%, IQR = −0.9%, 3.5%) compared to non-SMC (median = 11.5%, IQR = 8.8%, 14.0%) districts. For both TPR and uncomplicated malaria incidence the observed difference was also significant age disaggregated. The CAGR of severe malaria incidence showed that all age groups experienced a decline in severe malaria in both SMC and non-SMC districts. However, this decline was significantly higher in SMC (median = −22.3%, IQR= −27.6%, −18.2%) than in non-SMC (median = −5.1%, IQR= - 7.7; −3.6) districts for the entire population, as well as both CU5 and people over 5 years of age.ConclusionOur results provide evidence to support that—even in an operational programming context—adding SMC to the comprehensive package of malaria interventions yields a positive epidemiological impact and results in greater reduction in TPR, as well as the incidence of uncomplicated and severe malaria in CU5.