Objective To investigate the effects of dexmedetomidine combined with sufentanil on lung ischemia- reperfusion injury (LIRI) in rats. Methods SD rats were randomly divided into the sham operation group, model group, sufentanil group, dexmedetomidine group and sufentanil+dexmedetomidine group (n= 6 mice per group), and rats in these groups were given 20 μg / kg sufentanil, 25. 2 μg / kg dexmedetomidine and 20 μg / kg sufentanil + 25. 2 μg / kg dexmedetomidine, respectively. The LIRI model was then established. The lung tissue structure was observed by HE staining and TUNEL staining, and the mitochondrial damage of lung cells was observed by electron microscopy. The levels of SOD and MDA in lung tissues were detected by ELISA, and the protein levels of LC3B, Beclin1, ATG5, HO-1 and Nrf- 2 in lung tissues were detected by Western blot. Results Sufentanil and dexmedetomidine alone or together improved lung tissue damage, reduced lung cell apoptosis, alleviated mitochondrial swelling of lung cells and decreased the expression of SOD and MDA in LIRI rats. The three treatments also decreased the protein expressions of LC3B-Ⅱ, Beclin1 and ATG5 and the ratio of LC3B-Ⅱ/ LC3B-Ⅰ and increased the protein expressions of LC3B-Ⅰ, Nrf-2 and HO-1 in LIRI rats. Among the three treatments, the combination of sufentanil and dexmedetomidine had the best performance. Conclusions Dexmedetomidine, sufentanil and the combination effectively improved LIRI in rats. Dexmedetomidine and sufentanil have a synergistic effect on improving LIRI in rats, and the mechanism might be related to the activation of the NRF-2/ HO-1 antioxidant stress pathway and inhibition of excessive autophagy.