Manganese (IV) oxide nanoparticles (MnO NPs) are increasingly used in numerous applications. Multiple applications of MnO NPs, however, increase the human exposure and thus potential risk related to their toxicity. There is little information regarding the toxicity mechanisms of MnO NPs in human cells. In this study, we explored the toxic potential of MnO NPs in human breast cancer epithelial (MCF-7) and human fibrosarcoma epithelial (HT1080) cells in order to examine whether epithelial cells of different origins showed similar responses. Results demonstrated that MnO NPs induced cell viability reduction and membrane damage in both MCF-7 and HT1080 cells in a dose-dependent manner. MnO NPs were also found to induce pro-oxidants generation and antioxidants depletion in both cells. We further observed that MnO NPs induce apoptosis in both MCF-7 and HT1080 cells evident by altered regulation of apoptotic genes (p53, bax & bcl-2), cell cycle arrest and low mitochondrial membrane potential. Interestingly, we noticed that HT1080 cells were more susceptible to MnO NPs exposure than those of MCF-7 cells. This could be due to higher level of MnO NPs uptake into HT1080 cells as compared to MCF-7 cells. However, the mechanism of toxicity induced by MnO NPs in both MCF-7 and HT1080 cells was highly similar. This study warrants further research to delineate the underlying mechanisms of MnO NPs toxicity at in vivo level.