In this study, we demonstrated that both small molecule SR4 and niclosamide create energetic stress in melanoma irrespective of BRAF/NRAS status by uncoupling mitochondrial OXPHOS, decreasing intracellular ATP production, activating the energy sensor and metabolic tumor suppressor AMPK, and downregulating the mTOR pathway, leading to inhibition of tumor proliferation in vitro and in xenograft mice models. This evidence concerns the gene MTOR and melanoma.