Background: Colon cancer is the third leading cause of cancer-related deaths globally. Despite advances in systemic therapies, colorectal cancer still remains one of the foremost challenges due to high mortality rate. Objectives: In this current investigation, we observed the anticancer and proapoptotic potentials of ferruginol (FGL) in human colon cancer (HCT-116) cells. Materials and Methods: We recognized that the potentials of FGL against cell viability in HCT-116 cells were determined by MTT assay. Production of reactive oxygen species (ROS), status of mitochondrial membrane potential (MMP), catalase (CAT), superoxide dismutase (SOD), diminished glutathione (GSH), and thiobarbituric acid-reactive substances (TBARS) were also evaluated. In addition, apoptotic protein expressions such as bax, caspase-9, cytochrome-c, Bcl-2, and caspase-3 were assessed through Western blotting analysis. Results: Our findings showed that FGL induced apoptosis as confirmed through the thrashing of cell viability, improved ROS formation and TBARS, and decreased antioxidants (SOD, CAT, and GSH) and MMP in HCT-116 cells. Further, the proapoptotic role of FGL was downregulated the Bcl-2 expression, whereas improved caspase-9, Bax, caspase-3, and cytochrome-c expressions in HCT-116 cells. Conclusion: Therefore, FGL stimulates apoptosis in HCT-116 cells through triggering oxidative damage and mitochondrial-mediated apoptotic pathway.