Objective: To investigate the effect of dexmedetomidine against liver ischemia-reperfusion injury in rats by reducing endoplasmic reticulum stress. Methods: A total of 24 adult male Sprague-Dawley rats were randomly divided into sham operation group (6 rats, Sham group), liver ischemia-reperfusion injury group (6 rats, I/R group), and liver ischemia-reperfusion injury +dexmedetomidine pretreatment group (6 rats, I/R +Dex pretreatment group) (25 μg/kg intraperitoneally 30 min before ischemia), and liver ischemia-reperfusion injury +dexmedetomidine post-treatment group (6 rats, I/R +Dex post-treatment group) (25 μg/kg intraperitoneally 30 min after reperfusion). Hepatic ischemia-reperfusion injury model was performed by after clamping the hepatic hilum for 30 min and reperfusion for 6 h. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured by automatic biochemical analyzer. Malondialdehyde (MDA) and superoxide dismutase (SOD) activity were detected by enzyme-linked immunosorbent assay (ELISA). The pathological changes of each group were observed by HE staining. The expression of endoplasmic reticulum stress (P-PERK, P-IRE1α, CHOP) were detected by Western blot. Results: Compared with the Sham group, the serum levels of ALT and AST were significantly higher in the I/R group, compared with the I/R group, the serum ALT and AST in I/R+Dex pretreatment group and the I/R+Dex post-treatment group were significantly reduced; Compared with the Sham group, MDA activity in the liver tissue of the I/R group was significantly increased, while the SOD activity was significantly decreased, and the pathological score of the liver tissue was significantly increased; Compared with the I/R group, MDA activity and liver histopathology scores in I/R+Dex pretreatment group and the I/R+Dex post-treatment group were decreased, while SOD activity increased; The expression of P-PERK, P-IRE1α, CHOP in the I/R group were significantly higher than that in the Sham group, while the expression of the above indicators were reduced in I/R+Dex pretreatment group and the I/R+Dex post-treatment group. Conclusion: Dexmedetomidine can significantly attenuated liver ischemia-reperfusion injury in rats, which may be related to the reduction of endoplasmic reticulum stress.