Ficus carica L. (fig ) is one of the first cultivated crops and is as old as humans. This plant has been extensively used as a traditional medicine for treating diseases, such as cough, indigestion, nutritional anemia, and tuberculosis. However, the physiological activity of fig leaves on oral cancer is as yet unknown. In this study, we investigated the anticancer effect of methanol extracts of Ficus carica (MeFC) and the mechanism of cell death in human FaDu hypopharyngeal squamous carcinoma cells. MeFC decreased the viability of oral cancer (FaDu) cells but did not affect the viability of normal (L929) cells, as determined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay and Live and Dead assay. In addition, MeFC induced apoptosis through the proteolytic cleavage of procaspase-3, -9, poly (ADP-ribose) polymerase (PARP), downregulation of Bcl-2, and upregulation of Bax, as determined by 4′,6-diamidino-2-phenylindole dihydrochloride staining and western blot analysis. Moreover, a concentration of MeFC without cytotoxicity (0.25 mg/mL) significantly suppressed colony formation, a hallmark of cancer development, and completely inhibited the colony formation at 1 mg/mL. Collectively, these results suggest that MeFC exhibits a potent anticancer effect by suppressing the growth of oral cancer cells and colony formation via caspase- and mitochondrial-dependent apoptotic pathways in FaDu human hypopharyngeal squamous carcinoma cells. Therefore, the methanol extract of Ficus carcica leaves provide a natural chemotherapeutic drug for human oral cancer.