In the present study, the hexane extract from branches of (Winteraceae) displayed potent activity against parasites (100% mortality of the worms at 200 μg/mL). Bioactivity-guided fractionation afforded, in addition to the previously reported bioactive sesquiterpene 3,6-epidioxy-bisabola-1,10-diene, two chemically related drimane sesquiterpenes-polygodial () and 9-deoxymuzigadial (). The anti- effects for compounds and were determined in vitro, with compound demonstrating significant potency (EC value of 10 μM for both male and female worms), while was inactive. Cytotoxicity assays against Vero cells revealed no toxicity for either compound (CC > 200 μM). Additionally, an in silico analysis was conducted using the SwissADME platform for , revealing that this natural sesquiterpene exhibited adherence to several ADME parameters and no PAINS violations. Finally, in vivo studies with -infected mice treated with compound demonstrated a 44.0% reduction in worm burden, accompanied by decreases in egg production of 71.8% in feces and 69.5% in intestines. These findings highlight the potential of polygodial () as a promising prototype for schistosomiasis treatment.