BACKGROUND: Oral squamous cell carcinoma (OSCC) represents the majority of all cancers of the head and neck. In recent times, the development of antitumor drugs has been transformed from cytotoxic drugs to ameliorate the selectivity of the drug, overcoming multidrugresistant using natural alternatives. Amygdalin is one of the most common non-conventional anticancer drugs. Cisplatin has been used for the treatment of numerous human cancers. Recently combination therapy is the treatment of choice for cancer patients for the reason that it may enhance the efficiency of the combined agents and decreases their toxicities by decreasing the dose required for therapeutic benefits.AIM: This study was organized to investigate the cytotoxic effect of both amygdalin and cisplatin on OSCC, compare between two effects on OSCC, and investigate the synergistic effect on cytotoxicity of both drugs on OSCC. METHODS:The cytotoxic effect was determined using methyl tetrazolium assay, microscopic examination, and statistical analysis (ANOVA). RESULTS:Our findings showed that the cytotoxic effect of both drugs on HNO97 cells was dose-dependent. Microscopic examination showed that apoptotic criteria became more apparent in cisplatin/amygdalin mix-treated HNO97 group. Our statistical analysis results revealed significant differences in statistical analysis among mean values of NAF of 50 cells in each group, with lower mean values of NAF of mix 48 group (p < 0.0001). CONCLUSION:Both Amygdalin and cisplatin have anti-cancer effect on HN097 separately and their combination induced harmonious inhibitory effect on HNO97 cells.