Sclareol, a plant-derived diterpenoid widely used as a fragrance and flavoring substance, is well-known for its promising antimicrobial and anticancer properties. However, its activity on helminth parasites has not been previously reported. Here, we show that sclareol is active against larval (IC50 ≈ 13 μM), juvenile (IC50 = 5.0 μM), and adult (IC50 = 19.3 μM) stages of Schistosoma mansoni, a parasitic trematode responsible for the neglected tropical disease schistosomiasis. Microwave-assisted synthesis of Heck-coupled derivatives improved activity, with the substituents choice guided by the Matsy decision tree. The most active derivative 12 showed improved potency and selectivity on larval (IC50 ≈ 2.2 μM, selectivity index (SI) ≈ 22 in comparison to HepG2 cells), juvenile (IC50 = 1.7 μM, SI = 28.8), and adult schistosomes (IC50 = 9.4 μM, SI = 5.2). Scanning electron microscopy studies revealed that compound 12 induced blebbing of the adult worm surface at sublethal concentration (12.5 μM); moreover, the compound inhibited egg production at the lowest concentration tested (3.13 μM). The observed phenotype and data obtained by untargeted metabolomics suggested that compound 12 affects membrane lipid homeostasis by interfering with arachidonic acid metabolism. The same methodology applied to praziquantel (PZQ)-treated worms revealed sugar metabolism alterations that could be ascribed to the previously reported action of PZQ on serotonin signaling and/or effects on glycolysis. Importantly, our data suggest that compound 12 and PZQ exert different antischistosomal activities. More studies will be necessary to confirm the generated hypothesis and to progress the development of more potent antischistosomal sclareol derivatives.