Oral Submucous Fibrosis constitutes a severe condition affecting the lining of the mouth, which carries a risk of developing into oral squamous cell carcinoma, and seriously threaten individuals' lives. Currently, no specific treatment has been utilized to prevent OSF. The detailed mechanism of OSF is still elusive, and this study aims to clarify the mechanism of OSF. Methods: This study was conducted to elucidate the molecular mechanisms of the long noncoding RNA PDIA3P (lncRNA PDIA3P) and FAK/TGF-β pathway in OSF. The OSF mice model was established by injecting with injected with 1000 mg/L arecoline solution, then the blood samples and oral submucosal tissues were collected from all groups of rats for further testing. HE staining, immunofluorescence, Western blot, and qRT-PCR were then used to elucidate the molecular mechanisms of the molecular mechanisms of the lncRNA PDIA3P and FAK/TGF-β pathway in OSF. Results: The results showed that upregulation of the FAK/TGF-β signaling pathway can accelerate OSF process, while the downregulation of the FAK/TGF-β signaling pathway can prevent the OSF process. Similarly, enhanced activity of the lncRNA PDIA3P is implicated with OSF process, while reducing its level can served as a preventative method against the OSF development. Conclusion: Upregulating the lncRNA PDIA3P and FAK/TGF-β pathway can accelerate the process of OSF.