Ischemia–reperfusion (I/R) injury of the liver occurs in many clinical cases. Many steps are associated with hepatic I/R injury, including the release of many inflammatory molecules and infiltration of neutrophils into the liver. Recent studies revealed that hypertonic saline (HTS) has a strong anti-inflammatory effect and can inhibit a varity of neutrophil functions. So pretreatment with HTS may attenuate the liver injury associated with I/R. In this study, rats were divided into three groups: the sham group (S group), hepatic I/R group (I/R group), and HTS pretreatment group (HTS group). Serum ALT and myeloperoxidase (MPO) activity were determined. Serum tumor necrosis factor α (TNF-α) and interleukin 10 (IL-10) were determined by enzyme-linked immunosorbent assay (ELISA). Reverse transcription polymerase chain reaction analysis was used to assess the mRNA expressions of TNF-α and IL-10. Protein expressions of TNF-α, IL-10, STAT3, and phosphorylated STAT3 were analyzed by Western blot. Results showed that HTS pretreatment can augment the release of endogenous IL-10 by activating STAT3 in the process of hepatic I/R injury. Serum ALT levels, MPO activity in liver, generation of TNF-α, and infiltration of neutrophils in liver were inhibited in the HTS group. So we concluded that HTS pretreatment attenuates hepatic I/R injury by increasing the release of endogenous IL-10.