The development of safe and efficient drugs is urgently needed for clinical melanoma treatment. The repurposing of existing drugs for new clinical indications is an impressive strategy for the development of antitumor drugs. In this study, we embarred on an exploration of mebendazole, a well-established antiparasitic drug, to uncover its potential antimelanoma effect and underlying mechanisms. Our findings revealed that mebendazole possessed alluring antimelanoma activity with good safety profiles both in vitro and in vivo. Specifically, the antimelanoma function of mebendazole is derived from the inhibition of cell proliferation, migration and invasion, epithelial-mesenchymal transition (EMT), as well as the induction of endogenous apoptosis through reactive oxygen species (ROS)-mediated PI3K/Akt/mTOR pathway. Further studies have demonstrated that mebendazole can induce the accumulation of intracellular ROS driven by activating oxidative stress injury and causing a series of manifestations of mitochondrial functional failure. Successively, mitochondrial stress activated Ca2+-mediated and LKB1-mediated AMPK/mTOR/ULK1 pathway, which could trigger PINK1/Parkin-mediated mitophagy. Notably, the ability of mebendazole to induce apoptosis and inhibit proliferation in melanoma cells was related to the induction of PINK1/Parkin-mediated mitophagy. In summary, the present study revealed that mebendazole exerts attractive antimelanoma effects by acting on mitochondria to regulate ROS-mediated multiple signaling pathways.