The therapeutic administration of recombinant proteins is utilized in a multitude of research studies for treating various diseases. In this study, we investigate the therapeutic potential of Orosomucoid 2 (Orm2), an acute phase protein predominantly secreted by hepatocytes, for treating non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Our results show that high Orm2 expression prevents high-fat-diet (HFD)-induced obesity in mice. Pharmacological administration of recombinant ORM2 protein ameliorates hepatic steatosis, inflammation, hepatocyte injury, and fibrosis in mouse livers afflicted by NAFLD and NASH under dietary stress. Orm2 knockout mice develop spontaneous obesity under a regular diet and exacerbate HFD-induced steatosis, steatohepatitis, and fibrosis. Mechanistically, Orm2 deletion activates the Erk1/2-PPARγ-Cd36 signaling pathway, increasing fatty acid uptake and absorption in hepatocytes and mice. Overall, our findings underscore the critical role of Orm2 in preventing NASH and associated NAFLD in the context of obesity.