Whether bone marrow modulates systemic metabolism remains unknown. Our recent study suggested that myeloid-derived growth factor (MYDGF) improves insulin resistance. Here, we found that myeloid cell-specific MYDGF deficiency aggravated hepatic inflammation, lipogenesis, and steatosis, and show that myeloid cell-derived MYDGF restoration alleviated hepatic inflammation, lipogenesis, and steatosis. Additionally, recombinant MYDGF attenuated inflammation, lipogenesis, and fat deposition in primary mouse hepatocytes (PMHs). Importantly, inhibitor kappa B kinase beta/nuclear factor-kappa B (IKKβ/NF-κB) signaling is involved in protection of MYDGF on non-alcoholic fatty liver disease (NAFLD). These data revealed that myeloid cell-derived MYDGF alleviates NAFLD and inflammation in a manner involving IKKβ/NF-κB signaling, and serves as a factor involved in the crosstalk between the liver and bone marrow that regulates liver fat metabolism. Bone marrow functions as an endocrine organ and serves as a potential therapeutic target for metabolic disorders.