Echinococcus granulosus is a cestode parasite. The metacestode stage causes cystic echinococcosis (CE) mainly in the human liver and lung. Current chemotherapy against CE is based on mebendazole and albendazole. However, benzimidazoles result in a low cure rate or are ineffective in many patients; therefore, novel compounds for the treatment of this disease have been studied. Mefloquine was reported to be dramatically effective on cultured Echinococcus multilocularis metacestodes in vitro. And, nitazoxanide has a prominent protoscolicidal effect. However, these compounds have no impact on the growth of cysts harbored in mice. In this study, we investigated the in vitro and in vivo efficacy of mebendazole, mefloquine, and nitazoxanide against E. granulosus protoscoleces, germinal cells, and infected mice. The effect of mebendazole on protoscoleces and germinal cell was proved to be dose-dependent in vitro. And, a reduction of the cyst weight was also the found after oral application of mebendazole to infected mice. Mefloquine (5 and 10 μg/ml) caused death within 24 h of protoscoleces and germinal cells in vitro, whereas a lower concentration of 1 μg/ml was ineffective. In mice infected with E. granulosus, oral mefloquine (200 and 400 mg/kg twice weekly for 2 weeks) showed no reduction in parasite weight. Without affecting the viability of germinal cells and the growth of hydatid cysts, nitazoxanide only showed protoscolicidal effects in infected mice. In conclusion, mebendazole, mefloquine, and nitazoxanide showed various effects on E. granulosus under different conditions. These drugs could be useful to some extent in the treatment of CE.