Mitochondrial reactive oxygen species and reactive nitrogen species are proven to be major sources of oxidative stress in the cell; they play a prominent role in a wide range of human disorders resulting from nonapoptotic cell death. The aim of this study is to examine the cytoprotective effect of the NecroX series against harmful stresses, including pro-oxidant (tertiarybutylhydroperoxide), doxorubicin, CCl₄, and hypoxic injury. In this study, these novel chemical molecules inhibited caspase-independent cell death with necrotic morphology, which is distinctly different from apoptosis, autophagy, and necroptosis. In addition, they displayed strong mitochondrial reactive oxygen species and ONOO⁻ scavenging activity. Further, oral administration of these molecules in C57BL/6 mice attenuated streptozotocin-induced pancreatic islet β-cell destruction as well as CCl₄-induced hepatotoxicity in vivo. Taken together, these results demonstrate that the NecroX series are involved in the blockade of nonapoptotic cell death against mitochondrial oxidative stresses. Thus, these chemical molecules are potential therapeutic agents in mitochondria-related human diseases involving necrotic tissue injury.