Background and Aim: Oral squamous cell carcinoma is the most common neoplasm form in the oral cavity comprising 90% of all oral cavity cancers. It has been shown that natural compounds could exert significant anti-cancer effects on malignant cells. Amongst, Sophora pachycarpa, one of the sources of flavonoid compounds such as sophoraflavanone G (SG), possesses wide range of biological properties including anticancer effects. Therefore, this study was performed to investigate the cytotoxic effects of SG extracted from S. pachycarpa in combination with cisplatin/docetaxel on oral squamous cell carcinoma cells. Materials and Methods : To do so, SG was extracted from S. pachycarpa with more than 95% purity. The MTT assay was used to determine the cytotoxic effects of the drugs. To investigate the combinational effects of SG and drugs on KB cells, combination index (CI) was evaluated through the CompuSyn software. Results: The results showed that SG exhibited considerable cytotoxic effects on KB cells compared to HEK-293 cells. Despite normal cells, this compound enhanced anticancer activity of cisplatin/docetaxel against KB cells. The combination index showed that SG and cisplatin/docetaxel in low combinational concentrations produced synergistic cytotoxic effects on KB cells with a combination index values between 0.3-0.4. Alongside, SG+cisPt/DTX caused noticeable morphological changes that could be consider as an apoptotic indicator. Conclusion: These results suggested the potency of SG to enhance the anticancer activity of cisplatin/docetaxel on KB cell lines. While, it reduces the cytotoxic effects of cisPt/DTX on HEK-29 cells. Therefore, SG could be introduced as a promising candidate for the targeted treatment of oral cancer.