Background: Schistosomiasis mansoni is still a widespread parasitic infection especially among poor developing countries. Depending on praziquantel (PZQ) as a single medication for treatment and control, causes the emergence of isolates resistant to this drug. Continuous efforts are needed for the introduction of new effective therapies.  Some diuretics including spironolactone, showed promising anti-parasitic effects. Objectives: In this study, spironolactone, a potassium-sparing diuretic, was evaluated regarding its in vitro lethal effect on Schistosomamansoni (S. mansoni) adult worms using scanning electron microscopy (SEM). Material and Methods: A total of 144 worms; 72 males and 72 females were exposed to a concentration of 10 μg/ml of spironolactone for 5 days at 37±0.5°C in 5% CO₂ incubator. A pure medium and a medium containing 0.5% of dimethyl sulfoxide (DMSO) (vehicle) were used as negative controls, while PZQ at 10 μg/ml was used as a reference drug. The compound was then retested using the same technique by successive descending dilutions of the solution. Mortality rate of 50% (lethal concentration) (LC50) and 100% (lethal concentration) (LC100) were calculated after 72 h and 5 days exposure. Results: Our results highlighted the potent anti-schistosome effect of spironolactone as it showed 100% mortality of worms at 6.4 μg/ml and 5 μg/ml after 72 h and 5 days exposure, respectively. While 50% mortality of worms was obtained at 4.5 μg/ml and 3 μg/ml after 72 h and 5 days exposure, respectively. Moreover, SEM of male and female S. mansoni worms exposed to spironolactone in vitro, showed disintegration and sloughing of the tubercles on the dorsal surface of males, erosion of the tegument with exposure and appearance of the sub-tegumental tissue in males and females. Conclusion: Being a safe, oral, inexpensive, and well tolerated drug, spironolactone is capable of being a potent future anti-schistosome drug.