The main challenge in schistosomiasis control has been the emergence of drug-resistant parasites. Since the 1970's, praziquantel (PZQ) is the single drug for treatment. This fact highlights the importance to research news chemotherapeutic agents. In the last years, S. mansoni excretory system and tegument have been major targets for drug development. The purpose of this study was to evaluate the effect of sesquiterpenes, alpha-humulene and trans-caryophyllene on S. mansoni survival, excretory system and membrane integrity, after in vitro exposure. The in vitro studies, showed that sesquiterpenes reduced egg production and motor activity of worms at sublethal concentrations, and caused death in a concentration-dependent manner (100 and 200μg/mL). Tegumental analysis by Scanning Electron Microscopy (SEM), showed tegument damage. Additionally, it was possible to observe lesions, evidenced by intense marking trough Hoechst probe, in the tegument and suckers of worms exposed to 200μg/mL. In this study, we also showed that resorufin is only capable of identifying the interaction of sesquiterpenes in males excretory system, Pgp expression and inferring that females are more tolerant to treatments. Thus, the present study results contribute to an understanding of alpha-humulene and trans-caryophyllene effect over these targets, contributing for the development of schistosomicidal drugs.