Schistosomiasis mansoni is considered one of the most common fibrotic diseases resulting from inflammation and deposition of fibrous tissue around parasitic eggs trapped in the liver, causing morbidity and mortality. Chemotherapy against schistosomiasis is largely dependent on Praziquantel (PZQ). Yet, the huge administration of it in endemic areas and its incompetence towards the immature stages have raised serious alarms against the development of drug resistance. Few drugs are directed to reverse schistosomal liver fibrosis, particularly at the chronic and advanced stages of the disease. Recently, protein tyrosine kinase (PTK) inhibitors have been identified as potent anti-schistosomal and anti-fibrotic drugs against schistosomes, that may suppress and reverse Schistosoma mansoni (S. mansoni) induced liver fibrosis. The present study was designed to assess the anti-schistosomal and antifibrotic activity of Genistein, a PTK inhibitor, in comparison to PZQ, on both acute and chronic S. mansoni-infected mice using different parasitological, histopathological and immunohistochemical studies. Genistein showed a significant reduction (P < .05) in total worm burden, tissue egg load, mean hepatic granulomas diameter and numbers, percentage of collagen and expression of transforming growth factor-beta 1 (TGF-β 1) in the examined hepatocytes with elevation in percentage of degenerated ova, in comparison to the control groups, in both acute and chronic stages of infection. The best results were obtained when Genistein was combined with PZQ. Therefore, it was concluded that Genistein showed a promising anti-schistosomal and anti-fibrotic properties which could make it one of the new potential targets in chemotherapy against schistosomiasis.