Non alcoholic fatty liver disease (NAFLD) is a liver metabolic disorder that can progress to non alcoholic steatohepatitis, cirrhosis, and ultimately hepatocellular carcinoma (HCC). The miRNA miR 21 is upregulated in steatotic livers and is considered to exert powerful oncogenic functions. The mechanisms by which miR 21 promotes in vivo hepatic metabolic disorders and hepatocarcinogenesis are however still unclear. We therefore aimed at better delineating the in vivo roles of miR 21 in NAFLD and HCC pathogenesis. We demonstrated that mir-21 alters the expression of critical metabolic regulators of the liver to promote metabolic disorders induced by excessive energy intake in mouse, such as glucose intolerance, increased adiposity, hepatic insulin resistance and steatosis. We however also showed unexpected mir-21 tumor suppressive functions against chemically- and genetically-induced HCC, likely through a hepatic anti-inflammatory action. mir 21 silencing could thus constitute a therapeutic strategy for the treatment of metabolic pathologies, but might be detrimental when used against HCC.