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Excessive generation of reactive oxygen species (ROS) has been implicated in the progression of tumors. Superoxide dismutase 3 (SOD3) is a copper-containing secretory antioxidative enzyme that plays a critical role in redox homeostasis, particularly in extracellular spaces. Considerable evidence suggests that SOD3 protein expression is significantly decreased or lost in several tumor tissues, and this loss results in tumor metastasis. On the other hand, epigenetic disturbances, including DNA hyper-/hypomethylation, histone de/acetylation, and histone de/methylation, may be involved in tumorigenesis and the progression of metastasis. However, regulation of SOD3 in the tumor microenvironment and the involvement of epigenetics in its expression remain unclear. To elucidate the molecular mechanisms underlying SOD3 expression, we investigated the involvement of epigenetics, including DNA methylation and histone modifications, in its regulation in tumor cells and macrophages. SOD3 expression in human monocytic THP-1 cells and human lung cancer A549 cells was silenced by DNA hypermethylation within the SOD3 promoter region. Furthermore, the DNA demethylase, ten-eleven translocation 1, was shown for the first time to play a key role in regulation of DNA methylation within that region. We also demonstrated that myocyte enhancer factor 2 functioned as one of the transcription factors of SOD3 expression in THP-1 cells. Collectively, these novel results will contribute to the elucidation of epigenetic redox regulation, and may provide important insights into tumorigenesis and tumor metastasis.