Cancer is the most challenging medical condition to treat because of its high death and morbidity rates. For the past 20 years, its incidence has grown significantly. The second most common cause of cancer-related death worldwide in 2020, according to WHO data, is colon cancer, which accounts for 33% of all cancer cases. Radiation, chemotherapy, and resection surgery have recently been employed in colon cancer treatment. Even now, researchers are working to develop targeted therapy as well as additional cancer treatments, such as herbal therapy. In Asia, including China, India, Malaysia, Indonesia, and other countries, green betel (Piper betle L.) is a plant that is widely used as medicine. Among the bioactive substances found in green betel are hydroxychavicol, eugenol, chavicol, phenol, flavonoids, and compounds with significant antioxidant properties. The antibacterial, antiseptic, anti-inflammatory, and anticancer properties of green betel extract have been shown in earlier research. The purpose of this study is to ascertain the anticancer effects of Piper betle L. against colon cancer. This study utilized the HT-29 continuous culture cells which were treated with different Piper betle L. extract concentrations, ranging from 200, 400, to 800 μg/mL. Immunofluorescent was used to determine the expression of p-Akt and cleavage caspase-3 as apoptotic cell markers. Flow cytometry analysis was used to determine the number of cell death. Piper betle L. extract treatment had a promising anticancer effect on the HT-29 cells. At the molecular level, the extract decreased expressions of p-Akt, increased expression of cleavage caspase-3, and increased cell death. When applied to HT-29 colon cancer cells, green betel extract demonstrates strong potential anticancer properties. To develop the green betel as a treatment for cancer, particularly colon cancer, more research is required.