Background <p>Cepharanthine (CEP), a kind of isoquinoline alkaloid extracted from stephania, is applied in the treatment of cancer. This study aimed to explore the antitumor effects and specific mechanism of CEP on oral squamous cell carcinoma (OSCC) in vitro and in vivo.</p> Methods <p>The anticancer effects of CEP were studied by evaluating cell apoptosis, viability, migration, and invasion of OSCC cells. The epithelial-mesenchymal transition (EMT) related proteins levels were detected using qRT-PCR and western blot methods. Moreover, the N6-methyladenosine (m6A) modification of high mobility histone A2 (HMGA2) was determined by methylated RNA immune-precipitation (MeRIP) assay.</p> Results <p>We found that CEP suppressed the proliferation and EMT of OSCC cells. Moreover, CEP treatment increased the expression of METTL14 and suppressed m6A modification of FOXL2. Additionally, Overexpression of METTL14 reversed the effects of CEP and induced the aggressiveness of OSCC cells.</p> Conclusion <p>CEP impeded the proliferation and EMT of OSCC cells via m6A-induced inactivation of HMGA2/FOXL2 axis, relieving the carcinogenic behaviors of OSCC.</p>