IIonizing radiation exposure, whether accidental, occupational, or therapeutic, induces direct and indirect alterations. So, this study was carried out to investigate the effect of γ-radiation (IR) exposure on hepatic injury induced by high-fat diet (HFD). Three groups of thirty female Wister rats were formed. Rats in Group I were fed ordinary chow. HFD was provided to rats in the group II. In Group III, HFD-fed animals were subjected to a single dose of γ radiation IR (3.5 Gy). Blood and liver tissues were taken for analysis of biochemical parameters, gene expression, and protein levels, as well as lipid profile and endoplasmic reticulum (ER) stress. The lipid content in serum was dramatically increased after HFD feeding in HFD-fed and/or IR-exposed rats. Furthermore, when lipid buildup increased, ER stress was produced in the HFD group's liver via the IRE1 signaling pathway. Meanwhile, rats given HFD and exposed to IR suffered greater damage. Our findings showed that HFD-fed rats exposed to IR had higher disruptions in lipid metabolism and hepatic ER stress