BACKGROUND: Malaria epidemics are a well-described phenomenon after extreme precipitation and flooding, which account for nearly half of global disasters over the past two decades. Yet few studies have examined mitigation measures to prevent post-flood malaria epidemics. METHODS: We conducted an evaluation of a malaria chemoprevention program implemented in response to severe flooding in western Uganda. Children ≤12 years of age from one village were eligible to receive 3 monthly rounds of dihydroartemisinin-piperaquine (DP). Two neighboring villages served as controls. Malaria cases were defined as individuals with a positive rapid diagnostic test result as recorded in health center registers. We performed a difference-in-differences analysis to estimate changes in the incidence and test positivity of malaria between intervention and control villages. RESULTS: A total of 554 children received at least one round of chemoprevention with 75% participating in at least two rounds. Compared to control villages, we estimated a 53.4% reduction (aRR 0.47, 95% CI 0.34 - 0.62, p<.01) in malaria incidence and a 30% decrease in the test positivity rate (aRR=0.70, CI 0.50 - 0.97, p=0.03) in the intervention village in the six months post-intervention. The impact was greatest among children receiving the intervention, but decreased incidence was also observed in older children and adults (aRR=0.57, CI 0.38-0.84, p<.01). CONCLUSIONS: Three rounds of chemoprevention with DP delivered under pragmatic conditions reduced the incidence of malaria after severe flooding in western Uganda. These findings provide a proof-of-concept for the use of malaria chemoprevention to reduce excess disease burden associated with severe flooding.