Lung injury is a serious condition encountered following hepatic ischemia/reperfusion (IR). This study aimed to explore whether a dipeptidyl peptidase-4 inhibitor agent vildagliptin (V) could alleviate the lung injury caused by hepatic IR in a rat model and if so elucidate its molecular protective mechanism. Three groups of rats were used. Sham group: received normal saline and exposed to a sham operation, IR group: received normal saline and subjected to the operation of hepatic I (45 min)/ R (180 min), V+IR group: received for 10 days intraperitoneal injection of V (10 mg/kg/day). After reperfusion, liver and lung were collected for biochemical and histological evaluation. Hepatic IR exhibited significant elevation in serum alanine aminotransferase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) enzyme levels, serum and lung malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α) in addition to lung nitric oxide (NO) levels, hypoxia-inducible factor 1-alpha (HIF-1α) mRNA and protein levels, hepatocyte growth factor (HGF) mRNA expression, and inducible nitric oxide synthase (iNOS) mRNA and protein expressions in lung tissue along with a marked reduction in the serum and lung content of catalase in comparison to the sham group. Moreover, liver and lung injury in the IR group was detected by histopathological examination. Vildagliptin ameliorated markedly the biochemical changes as well as liver and lung architecture in comparison to the IR group. Vildagliptin mitigated the induced lung injury by hepatic IR via suppression of oxidative stress markers, pro-inflammatory cytokine TNF-α as well as the HIF1-α/iNOS/HGF expressions in lung tissue.