ObjectivesOral submucous fibrosis (OSMF) is a chronic inflammatory disease and a potentially malignant oral disorder. However, the best therapeutic treatment for OSMF remains uncertain. Our previous study showed that photobiomodulation (PBM) therapy and forskolin could reduce arecoline‐induced fibrosis reactions via the cAMP pathway. The present study aimed to establish an animal model of areca nut extract (ANE)‐induced OSMF and to evaluate the therapeutic potential of PBM and forskolin for ANE‐induced OSMF.Subjects and methodsThe mice were divided into five groups. The buccal tissues were harvested for histomorphological analysis and immunoblotting.ResultsOur results showed that PBM significantly reduced the development of ANE‐induced OSMF, quantified by changes in submucosal layer thickness and collagen deposition. Additionally, PBM could extensively reduce the protein expression of the fibrotic marker genes alpha‐smooth muscle actin (α‐SMA) and connective tissue growth factor (CTGF) in buccal submucous lesions. However, forskolin treatment significantly decreased the protein expression of fibrotic marker genes but slightly decreased the observed histomorphological changes.ConclusionsWe established an ANE‐induced OSMF mouse model, which also provided a model for the development of a therapeutic treatment for OSMF. The anti‐fibrotic effects of PBM and forskolin may be useful for clinical interventions.