Abstract Objectives Our study aimed to investigate the role of endoplasmic reticulum stress (ER) in brain damage following hepatic ischemia-reperfusion (HIR) injury. Specifically, we characterized the expression of markers of ER stress and histopathologic changes in the brain following HIR. Methods Twelve adults female Wistar rats were divided into two experimental groups equally. Group 1 was designed as the control group, and Group 2 was designed as the HIR group. Blood, liver, and brain tissue samples were collected during the sacrifice. The quantitative ELISA kits were used to detect glucose-regulated protein 78 (GRP-78), activating transcription factor 4 (ATF-4), eukaryotic initiation factor 2 alpha (EIF2-A), caspase-3, caspase-9, and CCAAT/enhancer-binding protein (CEBP) in plasma. Histopathological examination was performed for liver and brain tissues. Results Higher levels of GRP-78 (p=0.006), ATF4 (p=0.001), and EIF2-Α (p=0.007) were detected in group 2. More damage was detected in liver and brain samples in the histopathological examination of group 2 than in group 1. Conclusions Our results demonstrate that ER stress is involved in developing brain damage following hepatic ischemia-reperfusion injury, as evidenced by increased expression of markers of ER stress and neuronal injury.