Preventive chemotherapy with Praziquantel is the mainstay of schistosomiasis control. However, drug resistance is an imminent threat, particularly with large-scale administration of Praziquantel, in addition to much less efficacy against young schistosomes. Several biological activities of limonin have been explored such as insecticidal, insect antifeedant and growth regulating activity on insects as well as anti-malarial, antiviral, anticancer, cholesterol-lowering, and antioxidant activities. This study investigates limonin as an alternative antischistosomal compound using two novel, single, oral dose regimens. In the current work, the therapeutic efficacy of different limonin dosing protocols were evaluated in experimentally infected mice harbouring Schistosoma mansoni (Egyptian strain) juvenile or adult stages. Oral administration of limonin in a single dose of 50 or 100 mg/kg on day 21 post-infection (p.i.) resulted in a significant worm burden reduction of 70.0% and 83.33% respectively. The same dose given on day 56 p.i. reduced total worm burdens by 41.09% and 60.27%, respectively. In addition, significant reductions of 34.90% and 47.16% in the hepatic, and 46.67% and 56.1% in the intestinal tissue egg loads, respectively, associated with significant alterations in the oogram pattern with elevated dead egg levels. Limonin produced ameliorations of hepatic pathology with reduction in dimensions and number of granuloma’s. Limonin also produced a variety of tegumental alterations in treated worms including tubercular disruption, edema, blebbing and ulcerations. Results obtained by this work elucidated promising limonin bioactivity against S. mansoni juvenile and adult stages and provided a basis for subsequent experimental and clinical trials.