Cisplatin, a platinum-derived compound, has been used in treatment of various types of cancers including oral cancer. Despite its wide usage, cisplatin has multiple adverse effects affecting the systemic health of patients. Schisandrin C is a natural compound derived from Schisandra chinensis. Studies have shown its beneficial effects including antioxidant activity, hepatoprotective and renal protective actions. However, effect of schisandrin C on cisplatin-induced cytotoxicity has not been studied extensively. In this study, we examined the effect of schisandrin C treatment on YD-38 oral squamous carcinoma cell line, in combination with cisplatin treatment. Effect of schisandrin C on cisplatin-induced cell death was examined by MTT assay and live and dead cell staining. Changes in apoptosis-related intracellular signal, and ROS generation were measured by immunoblot and flow cytometry. Schisandrin C showed protective effect against cisplatin-induced cell death. Schisandrin C inhibited phosphorylation of JNK, expression of Bax, cleavage of caspase 3, and release of mitochondrial cytochrome c. In contrast, expression of Bcl2 and phosphorylation of Akt were increased by schisandrin C. Schisandrin C also suppressed intracellular reactive oxygen species generation. These results suggest that schisandrin C has a protective effect against cisplatin-induced cytotoxicity and showed a potential to be used in combination with cisplatin during chemotherapy to reduce side effects.