In the present study, we have demonstrated that melatonin could potentiate fisetin-mediated antitumor effect in melanoma cells through activating cytochrome-c/caspase-dependent-apoptotic pathway, downregulating expression of COX-2 and iNOS through regulating the nuclear translocation of NF-κB and p300 and abrogating their binding on COX-2 promoter. Here, CYCS is linked to melanoma.