Schistosomiasis is a major public health problem in Madagascar. World Health Organization recommends preventive chemotherapy by mass drug administration (MDA) with praziquantel as the primary approach to control Schistosoma mansoni related morbidity in endemic populations, alongside complementary interventions such as health education. The impact of annual MDA and health education programs was assessed in the hard-to-reach Marolambo District of eastern Madagascar, an area endemic for S. mansoni. Repeated cross-sectional studies undertaken 2015–2019 examined between 300 and 381 school-aged children (aged 5–14 years) annually. The prevalence and infection intensity of S. mansoni were assessed by urine-circulating cathodic antigen (CCA) dipsticks and coproscopy using Kato-Katz (KK) methodologies. After four rounds of annual MDA, a reduction in S. mansoni prevalence was seen in CCA (93.9% in Year 1 to 87.7% in Year 5; p=0.007) and KK (73.9% in Year 1 to 59.4% in Year 5; p<0.0001). Prevalence of heavy-intensity infections roughly halved from 23.7% to 10.1% (p<0.0001), and the mean intensity of infection fell by 55.0% (480.2 to 216.3 eggs per gram of feces). A malacological survey found Biomphalaria pfeifferi snail intermediate hosts in multiple water contact sites including rice paddies, streams and Nosivolo River. Despite reductions in infection prevalence and intensity, schistosomiasis still poses a significant public health challenge in Marolambo District. Twice yearly MDA cycles and/or community-wide MDA are suggested to better reduce infections. Expanding health education, improving standards of water, sanitation and hygiene, and attention on snail-related control will also be important, especially in rice paddy irrigated areas.