〔Abstract〕 Objective To investigate how the m6A methylation enzyme Methyltransferase like protein 16(METTL16) exerts its effects on the proliferation, migration and invasion of hepatocellular carcinoma(HCC) cells HepG2 and HCC-LM3, and to further explore the underlying molecular mechanism. Methods The overexpression and RNA interference vectors targeting METTL16 were transfected into HepG2 and HCC-LM3 cells and screened the stable cell lines by purimycin. The expressions of METTL16 were detected by means of qRT-PCR and Western blot assay; in HCC cell lines, Cell counting kit-8(CCK-8), Transwell assays, and flow cytometry were used to observe the effects in the proliferation, migration, invasion and cell cycle after transfection; Western blot assay was used todetect the effect of expression of VEGFA-VEGFR2 pathway-related proteins in hepatocellular carcinoma cells; Gene Expression Omnibus database was used to analyzethe expression levels of METTL16 in human liver cancer tissues and paraneoplastic tissues.Log-rank test was used to compare the clinic pathological characteristics between patients with high and low expression of METTL16 in hepatocellular carcinoma. Results Western blot and real-time quantitative PCR experiments showed that METTL16 overexpressing cell lines and interfering cell lines were successfully constructed in HepG2 and HCC-LM3 cells. CCK-8, Transwell and flow cytometry results showed that overexpression of METTL16 resulted in a decrease in the number of proliferating, migrating and invasive cells, and the number of cells in G2/M phase proportion increased. Western blot showed that overexpression of METTL16 inhibited the expression of VEGFA-VEGFR2 pathway-related proteins VEGFR2, p-AKT, Cyclin B, and CDK1 in HepG2 cells, but knockdown of METTL16 reversed the inhibition effect on these proteins.Compared to the matched non-tumor liver tissues, METTL16 was downregulated in HCC tissues; however, the levels of METTL16 were not significantly associated with the clinic pathological characteristics of HCC patients. Conclusion METTL16 may inhibit the proliferation, migration and invasion of HCC cells by inhibiting the VEGFR2 pathway.