Hepatic ischemia/reperfusion injury (H-IRI) is associated with irreversible liver damage. The current study aimed to investigate the protective effect of carvedilol against H-IRI in high-fructose high-fat diet (HFrHFD)-fed mice and the role of G protein-coupled receptor kinase 2 and 5 (GRK2 and GRK5). Mice were fed HFrHFD for 16 weeks; then mice were subjected to 30 min of ischemia followed by 1 h of reperfusion at the end of feeding period. Carvedilol (20 mg/kg, i.p.) was administered 30 min before ischemia. To explore the role of GRK2 and GRK5 in mediating carvedilol effects, paroxetine (GRK2 inhibitor, 10 mg/kg, i.p.) and amlexanox (GRK5 inhibitor, 25 mg/kg, i.p.) were administered 30 min before carvedilol administration. Liver function, histopathology and hepatic oxidative stress, as well as inflammatory and apoptotic markers were measured at the end of the experiment. In addition, adrenergic receptor downstream signals were measured in the liver. Results showed increased markers of liver injury (ALT and AST) in mice subjected to H-IRI. Moreover, liver injury was associated with slight collagen deposits as revealed by histopathology and elevated hepatic levels of oxidative stress, inflammatory and apoptotic markers. On the other hand, carvedilol protected mice against H-IRI and improved all associated pathological changes. Furthermore, pre-injection of either GRK2 or GRK5 inhibitor did not change carvedilol effects on serum ALT level and liver collagen deposits, while increased its antioxidant, anti-inflammatory and anti-apoptotic effects. In conclusion, carvedilol protects against H-IRI in HFrHFD-fed mice. GRK2 and GRK5 may not play a potential role in mediating this effect.