B Background: Oral cancer is one of the most common cancers, causing more than 5,780 deaths per year worldwide. Tinospora cordifolia and Clinancanthus nutans are plants that have the potential to be chemopreventive agents. Objective: To evaluate the potential cytotoxicity effect of ethanol leaves extract of T. cordifolia, C. nutans and combinations of T. Cordifolia and C. nutans against HSC-3 cell lines. Method: HSC-3 cells were treated with ethanol leaves extracts of T. cordifolia, C. nutans and combination of T. Cordifolia and C. nutans at various concentrations (10, 25, 50, 100 µg/mL) for 24 hours using the MTT assay. Data were analyzed by analysis of variance and post hoc Tukey’s test with P < 0.05. Result: The ethanol leaves extracts of T. cordifolia, C. nutans and the combination of T. cordifolia and C. nutans had a cytotoxic effect on HSC-3 cell lines, while the ethanol extract of the combination at a dose of 100 µg/mL had the highest effectiveness among all extract concentrations on HSC-3 cell lines. Conclusion: There is cytotoxicity effect of T. cordifolia, C. nutans and the combination of T. Cordifolia and C. nutans on HSC-3 cell lines.