Schistosomiasis mansoni leads to liver fibrosis that was believed to be irreversible once established leading to life-threatening complications in most cases. Praziquantel (PZQ) is considered the best drug in treatment, for decades. A universal approach towards drug repurposing is recommended, to be combined with other known drugs that may expand their efficiencies or/and discover new mechanisms of action of the used drugs. In this work Angiotensin-converting enzyme inhibitor (ACEI) “Lisinopril" was used alone or with Praziquantel (PZQ), versus long-duration PZQ (LD-PZQ) to test for their anti-fibrotic properties, applying Transforming Growth factor beta 1 (TGF-β1 ) as an indicator of activated fibrotic fibroblasts, to be automatically quantified within hepatic tissues of experimentally infected mice, using a software image analyzer. All treated groups showed significant reduction within TGF-β1 local hepatic expression, with the greatest reduction occurring among groups treated with LD-PZQ followed by those which received combined ACEI and PZQ.  The highest TGF-β1 local hepatic expression values were obtained by groups receiving the classic anti-bilharzial single oral dose praziquantel (S.O.D PZQ) regimen, indicating its ineffectiveness as a monotherapeutic agent to minimize liver fibro-sclerotic threats in acute and chronic phases of schistosomiasis. Lisinopril alone or when combined with PZQ, succeeded in causing a drop in TGF-β1 hepatic expression as LD-PZQ regimen, thus increasing the chance of healing without hepatic scarring. Yet, its usage as an adjuvant to PZQ, instead of LD-PZQ has the additional benefit of not exposing the community to unwarranted resistance to PZQ, a drug that is to date still indispensable for the treatment of bilharziasis.