N6-methyladenosine (m6A) is involved in the development of non-alcoholic fatty liver disease (NAFLD). Here, we aimed to investigate the effect of m6A methyltransferase METTL3 on liver damage in high-fat diet (HFD)-induced mouse model and hepatocyte damage treated with free fatty acid (FFA). Plasma lipid, lipogenesis, viability, and apoptosis were measured to assess injury. m6A methylation was evaluated using m6A dot blot, methylated RNA immunoprecipitation, dual-luciferase reporter assay, and RNA decay assay. The results indicated that METTL3 was highly expressed in the liver of HFD mice, which knockdown improved plasma lipid and reduced liver lipids. Additionally, silencing of METTL3 promoted cell viability, inhibited apoptosis, reduced lipid concentrations, and downregulated lipogenesis-related marker levels. Moreover, METTL3 promoted the m6A methylation of FAS and enhanced its stability. In conclusion, silencing of METTL3 attenuates the progression of NAFLD by FAS m6A methylation, suggesting that METTL3 may be a promising target for treating NAFLD.