Abstract: Objective To investigate the signaling pathways that mediate the protective effects of dexmedetomidine on lung tissue against ischemia-reperfusion (I/R) injury during cardiopulmonary bypass (CPB). Methods Forty adult SD rats were randomized into 5 groups, namely I/R group (group A), dexmedetomidine group (group B), sham-operated group (group C), oxypenicillin group (group D), and oxypenicillin + dexmedetomidine group (group E). The arterial blood gas, lung tissue apoptosis rate, protein kinase (Akt), phosphorylated Akt (p-AKT), caspase-3 and caspase-9 were compared among the 5 groups. Results In groups A, B, D and E, the heart rate (HR), mean arterial pressure (MAP), and oxygenation index (OI) measured before CPB, at opening of the left hilar and at the end of experiment decreased gradually while the respiratory index (RI) increased at the 3 time points. At the end of experiment, HR, MAP, and OI in group B were significantly higher and RI was significantly lower than those in groups A, D and E (P<0.05). In groups A-E, the pathological scores of the lung tissue at the end of the experiment were 4.89, 1.89, 0, 6.01 and 5.76, respectively, and the cell apoptosis rates in the lung tissue were 6.25%, 3.69%, 1.06%, 8.06% and 7.79%, respectively (P<0.001). Western blotting showed that the expressions of Akt and p-AKT were the highest and those of caspase-3 and caspase-9 were the lowest in group B among the 5 groups (P<0.05). Conclusion Dexmedetomidine can effectively alleviate lung injury in rats during CPB possibly by targeting caspase-3 and caspase-9 proteins that are related to PI3K/Akt signaling pathway.