How to improve the selectivity and efficacy of anticancer agents and to reduce side effects has always been a big challenge in clinical cancer therapy. Chemotherapeutic agents are usually toxic to both cancer and normal tissues, thus rendering compromised overall clinical outcome. Here we developed zero-valent iron nanoparticles (ZVI NPs) that exhibited selectivity toward higher toxicity to most cancerous cells thus opening a new era of anti-cancer therapy or adjuvant therapy through a novel molecular signaling pathway. We used head-and-neck cancer (HNC) cells and ovarian cancer (OVCA) cells to test the anti-cancer properties of ZVI NPs. The ZVI NPs served as a strong reactive oxygen species (ROS) inducer and caused irreversible mitochondria membrane potential lost in sensitive cancer cells that lead to cancer cell autophagy and growth suppression, while not significantly affect normal cell population. Further, the cytotoxicity of the ZVI NPs is highly depended on its redox state as oxidation of the NPs upon aging reduced their cytotoxic potency. In vivo study revealed a dose dependent tumor size reduction in tumor-bearing mice model without significant weight loss and pathological signs. These results suggest that ZVI NPs may serve as a new class of anticancer agent for a wide spectra of neoplastic diseases.