Background: Oral squamous cell carcinoma is a neoplasm of keratinocyte cells of oral mucosa epithelium that can potentially spread through lymphatic tissue or blood vessel. Although areca nut is one of the plants with a risk of inducing that cancer, areca nut is believed to have high antioxidant properties. Due to the current interest in the apoptosis effects from areca nut for oral cancer treatment, we investigated its ability to induce apoptosis and caspase-3 activity in oral cancer cell lines: HSC-2 and HSC-3. Methods: We examined the effect of areca nut on apoptosis and caspase-3 activity in HSC-2 and HSC-3 cells. Flow cytometry was conducted for the quantification of the cells that were apoptotic and expressing the caspase-3 enzyme for 24 and 48 hours. Results: Areca nut induced a significant increase (p<0.01) in late apoptosis of HSC-2 cells and mostly occurred over 48 hours. The study also found that in HSC-3, there were significant increases (p<0.01) the percentage of cells in early apoptosis after 24 hours and late apoptosis at 48 hours. Caspase-3 activity increased after 24 and 48 hours of areca nut exposure in both cells. Conclusions: The study showed that areca nut could be considered as a potential anticancer agent through its capability in inducing a caspase-dependent apoptosis.