BACKGROUND: It has been observed that methyltransferases-like 5 (METTL5) is a key mediator underlying tumorigenesis in humans. This study aimed to investigate the biological function, expression pattern, and clinical significance of METTL5 in oral squamous cell carcinoma (OSCC). METHODS: Bioinformatics interrogations and immunohistochemical staining were utilized for determining the expression and localization of METTL5 in OSCC, and revealing the relationship between the expression of METTL5 and prognosis. Cell phenotype experiments and xenograft models were used to detect the impact of METTL5 silencing on OSCC. Gene Set Enrichment Analysis, Spearman correlation, and c-Myc overexpression plasmid was utilized for exploring the regulatory effects of METTL5 on the Myc pathway. RESULTS: METTL5 was overexpressed in OSCC and correlated with reduced survival. Cell proliferation, migration, and invasion were significantly inhibited by METTL5 knockdown in vitro, and tumor growth was impaired in vivo. Moreover, METTL5 was capable of activating the Myc pathway. The influences of knockdown of METTL5 on Cal27 cell biological behaviors were reversed by overexpression of c-Myc. CONCLUSIONS: Our data suggested that METTL5 may act as a putative oncogene and prognostic biomarker in OSCC. The Myc pathway appears to be involved in cell proliferation, migration, invasion, and apoptosis in OSCC mediated by METTL5.