Oral squamous cell cancer (OSCC) is a major cause of death in developing nations. Chemoprevention could be an effective approach for averting buccal mucosa carcinoma. Bergapten (BG) is a known furanocoumarin, a natural psoralen derivative extracted from several types of citrus and bergamot oil, which has exhibited anti-inflammatory, anticancer, and apoptotic properties. This current research investigates the chemopreventive efficacy of BG against 7,12 dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch carcinogenesis (HBPC). OSCC was developed by painting DMBA (0.5%) in the HBP for 10 weeks and administering the effective dosages of BG (25 and 50 mg/kg bw) for 14 weeks. We investigate the tumor incidence, tumor burden, lipid peroxidation (LPO), antioxidants, xenobiotic enzymes, body weight changes, histopathological changes (H&E and PAS), immunohistochemistry, and quantitative real-time polymerase reaction (qRT-PCR) analysis. Administration of BG (25 and 50 mg/kg bw) dose-dependently inhibited (p < 0.05) tumor incidence and tumor burden and reversed the levels of the LPO, antioxidants, hepatic xenobiotic enzymes, body weight loss, and biochemical markers in the DMBA-stimulated hamsters. Furthermore, BG expressively elevated pro-apoptotic enzyme expressions (Bax, caspase-9, and caspase-3), while attenuating the B-cell lymphoma/leukemia type 2 (Bcl-2), inflammatory cytokines, and PI3K/Akt/mTOR signalling. These outcomes propose that BG employs chemopreventive and anticancer activity in DMBA-induced OSCC by triggering intrinsic apoptosis via repressing downstream inflammatory signalling cascades.