Background: Larval stage of Echinococcus granulosus is the main cause of the hydatid cyst. Surgery, which is both aggressive and high-risk, is the most common treatment for this type of cyst. Some medicines, such as mebendazole, are also used as a complementary approach to preventing the recurrence of hydatid cysts. Objectives: Considering the approved antiparasitic effects of sodium valproate (VPA) on some parasites, this research intended to examine the potential of VPA against protoscolices and hydatid walls. Methods: Liver hydatid cysts caused by E. granulosus were collected from a slaughterhouse. Protoscolices and hydatid cysts were exposed to RPMI and dimethyl sulfoxide (DMSO) media (control groups) or different concentrations of VPA and mebendazole in vitro. The viability of protoscolices was evaluated via light microscopy. Also, tissue changes and expression of apoptotic caspase-3 were examined in hydatid cyst walls (HCWs) using histological and immunohistochemical methods, respectively. Results: The mortality rates of VPA-treated and mebendazole-treated protoscolices were dose- and time-dependent. There was a significant difference between the intervention and control groups (P < 0.05). Tissue changes and apoptosis were observed in VPA-treated and mebendazole-treated HCWs. Conclusions: Valproate and mebendazole had significant effects on protoscolices and HCWs, although VPA exerted its effects more rapidly. It seems that VPA can be a new promising protoscolicidal agent and anti-hydatid medicine.