Schistosoma mansoni infection negatively impacts children's physical health and may influence general well-being. Schistosomiasis control programs aim at reducing morbidity through mass drug administration (MDA). This study aimed to compare morbidity markers between two cohorts of Tanzanian schoolchildren with initial high prevalence of S. mansoni infection. One cohort (N = 254 at baseline) received annual MDA for 4 years using community-wide treatment (CWT). The second cohort (N = 318 at baseline) received school-based treatment (SBT) every other year for 4 years. At year 5, the CWT cohort and the SBT cohort were reduced to 153 and 221 children, respectively. The characteristics of the 198 children lost to follow-up did not differ at baseline from those who were examined in year 5. Schistosoma mansoni infection, hemoglobin (Hb) and anemia, physical fitness, and perceived quality of life were investigated at baseline, year 3, and year 5, whereas liver and spleen pathology (ultrasound) were investigated only at baseline and year 5. Cohorts were compared using two-way mixed-model ANOVA. Both treatment regimens significantly decreased individual-level mean intensity of S. mansoni infection, anemia, and hepatomegaly, and increased Hb levels after 5 years. Hepatomegaly was the only parameter affected by the treatment regimen as the CWT approach reduced the percentage of individuals with hepatomegaly significantly more than the SBT approach. Both treatment regimens led to reduced physical fitness at year 5 compared with baseline. The modest impact of the two control strategies are probably due to initial low intensity of infection, ensuring low level of schistosomiasis-related morbidity.