The endoplasmic reticulum (ER)‐resident basic leucine zipper (bZIP) transcription factor c‐AMP responsive element binding protein H (CREBH/CREB3L3) is exclusively expressed in the liver and intestine. Physiologically, CREBH is intrinsically linked to nutritional homeostasis via its regulation on fatty acid β‐oxidation, lipid droplet process, very low‐density lipoprotein metabolism, gluconeogenesis, and iron metabolism. Pathologically, CREBH enhances hepatic acute‐phase response gene expression (e.g., C‐reactive protein and serum amyloid P‐component) and mediates nutrient‐surplus induced metabolic inflammation. Hyperactivation of CREBH in metabolic inflammation further contributes to the development of hyperlipidemia, lipotoxicity, non‐alcoholic fatty liver disease, and potentially non‐alcoholic steatohepatitis. This review highlights recent findings that delineate the interactions between CREBH and peroxisome proliferator activated receptor α (PPARα), fibroblast growth factor 21 (FGF21), fat‐specific protein 27 (FSP27), and lipoprotein metabolism with a focus on the molecular and biochemical mechanisms that underlie the development of metabolic inflammation, non‐alcoholic fatty liver disease and inflammatory associated bone disease.