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Hepatic ischemia-reperfusion injury (HIRI) is one of the major sources of mortality and morbidity associated with hepatic surgery. Ac2-26, a short peptide of Annexin A1 protein, has been proved to have a protective effect against IRI. However, whether it exerts a protective effect on HIRI has not been reported. The HIRI mice model and the oxidative damage model of H2O2-induced AML12 cells were established to investigate whether Ac2-26 could alleviate HIRI by regulating the activation of IL-22/IL-22R1/STAT3 signaling. The protective effect of Ac2-26 was measured by various biochemical parameters related to liver function, apoptosis, inflammatory reaction, mitochondrial function and the expressions of IL-22, IL-22R1, p-STAT3Tyr705. We discovered that Ac2-26 reduced the Suzuki score and cell death rate, and increased the cell viability after HIRI. Moreover, we unraveled that Ac2-26 significantly decreased the number of apoptotic hepatocytes, and the expressions of cleaved-caspase-3 and Bax/Bcl-2 ratio. Furthermore, HIRI increased the contents of malondialdehyde (MDA), NADP+/NADPH ratio and reactive oxygen species (ROS), whereas Ac2-26 decreased them significantly. Additionally, Ac2-26 remarkably alleviated mitochondria dysfunction, which was represented by an increase in the adenosine triphosphate (ATP) content and mitochondrial membrane potential, a decrease in mitochondrial DNA (mtDNA) damage. Finally, we revealed that Ac2-26 pretreatment could significantly inhibit the activation of IL-22/IL22R1/STAT3 signaling. In conclusion, this work demonstrated that Ac2-26 ameliorated HIRI by reducing oxidative stress and inhibiting the mitochondrial apoptosis pathway, which might be closely related to the inhibition of the IL-22/IL22R1/STAT3 signaling pathway.