Cisplatin [cis-dichlorodiammine platinum (II), CDDP], morphine (Mor), and electromagnetic field (EMF) induced oxidative stress. In this study, we tried to increase the cytotoxicity of CDDP in combination with Mor and/or EMF in MCF-7 and SH-SY5Y cells. Furthermore, we evaluate the expression levels of 11 antioxidant genes in both cell lines. We designed four treatments: CDDP alone, "CDDP+Mor," "CDDP+EMF," and "CDDP+Mor+EMF." Serial dilutions of CDDP, Mor (5.0 μM), and EMF (50 Hz, 0.50 mT, "15 min field-on/15 min field-off") were used for estimation of relative IC50 values. The mRNA expression levels of antioxidant genes were determined by real-time PCR. The IC50 value of CDDP in "CDDP+Mor+EMF" treatment was significantly higher than CDDP alone and "CDDP+Mor" treatments in both cell lines. Whereas the expression levels of antioxidant genes in the four treatments showed similar patterns in MCF-7 cells, in SH-SY5Y cells, most of the antioxidant genes showed an upregulation with "CDDP+EMF" and "CDDP+Mor+EMF" treatments. Moreover, significant differences in the number of upregulated genes were observed between different treatments in SH-SY5Y cells. The molecular mechanism of CDDP-reduced cytotoxicity in our designed combinations is probably different in MCF-7 and SH-SY5Y cells. CDDP in combination with EMF could protect SH-SY5Y cells from the cytotoxicity, whereas it has no significant change in MCF-7 cells.