Background and Aims: Nonalcoholic fatty liver disease (NAFLD), a complex metabolic syndrome, has limited therapeutic options. Microsomal prostaglandin E synthase‐2 (mPGES‐2) was originally discovered as a prostaglandin E2 (PGE2) synthase; however, it does not produce PGE2 in the liver. Moreover, the role of mPGES‐2 in NAFLD remains undefined. Herein, we aimed to determine the function and mechanism of mPGES‐2 in liver steatosis and steatohepatitis. Approach and Results: To evaluate the role of mPGES‐2 in NAFLD, whole‐body or hepatocyte‐specific mPGES‐2–deficient mice fed a high‐fat or methionine‐choline‐deficient diet were used. Compared with control mice, mPGES‐2–deficient mice showed reduced hepatic lipid accumulation, along with ameliorated liver injury, inflammation, and fibrosis. Furthermore, the protective effect of mPGES‐2 deficiency against NAFLD was dependent on decreased cytochrome P450 4A14 and increased acyl‐CoA thioesterase 4 levels regulated by the heme receptor nuclear receptor subfamily 1 group D member 1 (NR1D1), but not PGE2. Heme regulated the increased NR1D1 activity mediated by mPGES‐2 deficiency. Further, we confirmed the protective role of the mPGES‐2 inhibitor SZ0232 in NAFLD therapy. Conclusion: Our study indicates the pathogenic role of mPGES‐2 and outlines the mechanism in mediating NAFLD, thereby highlighting the therapeutic potential of mPGES‐2 inhibition in liver steatosis and steatohepatitis.