Kahweol, the coffee‐specific deterpene, has been shown to have potential anti‐cancer effects against several cancers. However, the molecular mechanisms underlying the anti‐cancer activity of kahweol have not yet established. In this study, we investigated whether kahweol could show anti‐cancer effects on oral squamous cell lines (OSCCs), HN22 and HSC4. We conducted an 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxy‐phenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium (MTS) assay, 4′‐6‐diamidino2‐phenylindole (DAPI) staining, propidium iodide staining, immunocytochemistry, and Western blot analysis for the characterization of kahweol and the underlying signaling pathway. We determined that kahweol‐treated cells showed significantly decreased cell viability and increased nuclear condensation and an increased sub‐G1 population in OSCCs. Interestingly, suppression of the transcription factor specificity protein 1 (Sp1) was followed by induced apoptosis by kahweol in a dose‐dependent manner. In addition, kahweol modulated the protein expression level of the Sp1 regulatory genes including cell cycle regulatory proteins and anti‐apoptotic proteins, resulting in apoptosis. Taken together, results from these findings suggest that kahweol may be a potential anti‐cancer drug candidate to induce apoptotic cell death through downregulation of Sp1 in OSCCs. Copyright © 2014 John Wiley & Sons, Ltd.