Schistosomosis is a worldwide tropical disease primarily caused by Schistosoma mansoni. Praziquantel is the only available drug for controlling schistosomosis, with many challenges. This study aims to evaluate the in vitro anti-Schistosoma effect of Ganoderma lucidum (G. lucidum) against adult and larval stages of Schistosoma based on the prediction of the binding activity of G. lucidum protein with proteins of various stages of S. mansoni by molecular docking to confirm its inhibitory potential through an insilico study. Results showed that Leu143, Ser165, Met214, and Asn213 were the primary crucial amino acids involved in the binding, with a promising large area of interactions between the two studied proteins. The in vitro study evaluated the motility and survival of adult and larval stages, compared to praziquantel and niclosamide, respectively. There was a significant reduction in the motility of adults after the two-hour incubation, with all concentrations and 100% death of all parasites with the minimal concentration (10μg/ml) within 4 and 6 h of incubation (P<0.01). Regarding the cercariae, at a concentration of 10 μg/ml, all the cercariae died (P<0.01) after 15 min, and the miracidial complete mortality rate (100%) (P<0.01) occurred at a concentration of 10 μg/ml after 8 min. This study first predicted the binding activity of G. lucidum protein with proteins (100%) of S. mansoni at various stages and proved the anti-Schistosoma effect of G. lucidum in vitro, considered a promising treatment for schistosomosis Keywords: Schistosoma mansoni, Ganoderma lucidum, in silico, molecular docking, in vitro