OBJECTIVE: Oral submucous fibrosis (OSF) is a chronic oral mucosal disease, which exerts a profound impact on patients' daily life and currently lacks efficacious therapeutic interventions. Epigallocatechin-3-gallate (EGCG), the abundant polyphenol found in green tea, exhibits remarkable anti-fibrotic effects on the skin. However, the research on OSF regarding EGCG is relatively limited. PURPOSE: We aimed to investigate the potential therapeutic effect of EGCG against OSF using an arecoline (ARE) -induced rat model and primary rat oral fibroblasts. METHODS: Primary rat oral mucosal fibroblasts (ROMF) were isolated and identified. Optimal ARE concentrations were established using the Cell Counting Kit-8. The impact of ARE on extracellular matrix (ECM)-related protein expression was assessed through RT-qPCR and Western blot techniques. Similarly, the effects of EGCG on ARE-induced ECM changes in ROMF were evaluated. The study also established an OSF model in Sprague-Dawley rats, induced by ARE, with pathological changes characterized using HE and Masson's staining, further assessing the impact of ARE on ECM-related protein expression in rat oral tissues through RT-qPCR and Western blot methods. RESULTS: EGCG effectively suppressed the ARE-induced ECM components while concurrently improving the OSF pathological process CONCLUSION: The results indicate that the natural product EGCG effectively suppressed the increased ECM components induced by ARE and concurrently improved the OSF pathological process, indicating that EGCG could be potentially a novel anti-fibrotic candidate drug for the treatment of OSF.