Aims: Non-alcoholic fatty liver disease (NAFLD) is a metabolic- related disorder ranging from simple steatosis to more severe forms, but the exact mechanism of progression remains unknown. MicroRNAs(miR), a class of small noncoding RNAs, are implicated in controlling a variety of biological processes. The aim of this study is to investigate the regulatory and protective role of miR-22-3p in NAFLD progression. Methods: Both in vitro and in vivo models of NAFLD were generated by treating HepG2 and Huh-7 cells with palmitic acid (PA) and by feeding mice a high-fat diet (HFD), respectively. HE and Oil Red O staining were used to examine liver tissue morphology and lipid deposition, respectively. qRT-PCR (quantitative real time polymerase chain reaction) was used for investigate expression of miR, SIRT1, and proteins involved in lipogenesis Results: HFD-mice hepatic tissues and PA-treated HepG2 and Huh-7 cells presented excess lipid production. Both in vitro and in vivo NAFLD model displayed decreased miR-22-3p and SIRT1 expression as evidenced by qRT-PCR. Overexpression of miR-22-3p induced downregulation of FAS, PPAR gamma and SREBP-1c via upregulation of SIRT1 expression. Reduction of hepatic lipid accumulation was observed by Oil red O staining. Conclusions: In this study, miR-22-3p had a role in ameliorating hepatic lipogenesis by regulation of SIRT1 signal pathway in NAFLD model. The overexpressed miR-22-3p protects hepatocytes from lipid metabolism and suppresses hepatic lipogenesis, suggesting as a potential target for the therapeutic strategy of NAFLD.