Single-dose targeted praziquantel preventive chemotherapy is the WHO-recommended intervention for schistosomiasis control in endemic countries. The objective of this study was to assess the efficacy and safety of single-dose praziquantel among Schistosoma mansoni-infected children in north-western Tanzania. A prospective safety and efficacy surveillance study was conducted among 341 school-going children treated with a single-dose praziquantel 40 mg/kg body weight. Socio-demographic, pre-treatment, and post-treatment stool examination and safety data were collected. The primary and secondary outcomes were treatment efficacy (parasitological cure and egg reduction rates at three weeks post-treatment) and treatment-related adverse events, respectively. The overall cure rate and egg reduction rate were 81.2% (76.8–85.3%) and 95.0% (92.7–97.3%), respectively. There was no significant association between cure rate and pre-treatment infection intensity. The incidence of treatment-associated adverse events was 28.5% (23.7–33.3%), with abdominal pain being the most common. Post-treatment abdominal pain and vomiting were significantly associated with pre-treatment infection intensity (p < 0.001) and anemia (p = 0.03), respectively. Praziquantel single-dose is still safe and efficacious against Schistosoma mansoni infection. However, the lack of cure in about one-fifth and adverse events in a quarter, of the infected children indicate the need for close praziquantel safety monitoring and treatment optimization research to improve efficacy.