Objectives The goal of this study is to investigate the chemopreventive efficacy of α-tomatine (AT) against DMBA-induced oral carcinogenesis, and its role in regulating Notch signaling and apoptosis.  Background Oral squamous cell carcinoma (OSCC) represents a significant public health challenge in India, frequently identified at advanced stages. The abnormal activation of the Notch signaling pathway plays a significant role in the progression of oral cancer. Natural phytochemicals like AT may provide effective and safe strategies for chemoprevention. Methods Oral carcinogenesis was induced in Syrian hamsters using 7,12-dimethylbenz[a]anthracene (DMBA). AT was administered orally at doses of 10, 20, and 40 mg/kg body weight. Tumor incidence, volume, and burden were assessed. Histopathological analysis was performed, and molecular mechanisms were evaluated using Western blotting for apoptotic markers and RT-PCR for Notch pathway genes. Results DMBA treatment resulted in 100% tumor incidence with marked tumor burden and histological features of squamous cell carcinoma. AT significantly reduced tumor incidence, volume, and burden in a dose-dependent manner, with complete tumor prevention at 40 mg/kg. Histopathological analysis revealed a reduction in dysplasia and carcinoma. It reinstated pro-apoptotic proteins (p53, p21, Bax), inhibited anti-apoptotic proteins (Bcl-2, Bcl-xL), and reduced the expression of Notch signaling genes. Conclusion Therefore, AT demonstrates significant chemopreventive properties against oral carcinogenesis through the inhibition of Notch signaling and the induction of apoptosis