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Oral squamous cell carcinoma (OSCC) is a predominant head and neck malignancy with epigenetic alterations key to its development; however, the role and mechanisms of methyltransferase 5, N6-adenosine (METTL5) in OSCC remain to be elucidated. This study aimed to investigate the functional role and underlying mechanism of METTL5 in OSCC progression. Western blotting analyzed METTL5 expression in OSCC cell lines and tissues, whilst Cell Counting Kit-8, Transwell, colony formation and wound healing assays, as well as cell cycle analysis and nude mouse xenografts were used to assess its functional effects. Moreover, ribosome nascent-chain complex-bound messenger RNA sequencing (RNC-seq) was used to assess gene translation efficiency (TE). Western blotting, Transwell and colony formation assays, and cell cycle analysis were employed for downstream studies. Bioinformatics analyses were conducted to complement mechanistic exploration. The Cancer Genome Atlas data demonstrated that higher METTL5 expression in metastatic head and neck squamous cell carcinoma tissues was significantly associated with poor prognosis. Furthermore, METTL5 knockout significantly inhibited OSCC tumorigenesis and metastasis in vitro and in vivo. Finally, RNC-seq identified 3,391 genes with reduced TE, with cyclin D3 (CCND3) shown to be a downstream target. In conclusion, METTL5 may promote OSCC progression by regulating CCND3 via N6-methyladenosine-mediated ribosomal methylation, positioning it as a potential therapeutic target in the future.