Necroptosis has been recently confirmed as a non-apoptotic form of programmed cell death. Discovery of novel chemical entities, capable of inducing necroptosis of cancer cells, is likely to act as an alternative strategy for dealing with drug resistance clinically. In this study, the identification of a novel Pleuromutilin derivative (compound <b>38</b>) is presented, capable of significantly increasing the cellular level of ROS and inducing melanoma cancer cell death via necroptosis. Furthermore, compound <b>38</b> noticeably ablated various cancer stem cells and inhibited the growth of melanoma cancer cells both <i>in vitro</i> and <i>in vivo</i>. Moreover, <b>38</b> exhibited low toxicity in animal models and excellent PK properties, which is currently being verified as a potential anticancer drug candidate.