Purpose: To investigate the protective effect of penehyclidine hydrochloride (PHC) on cardiopulmonary bypass (CPB)-related lung injury in rats. Methods: Thirty-six rats were divided into control, CPB and PHC groups. The CPB model was established in CPB and PHC groups. In PHC group, 2-mg/kg PHC was added to the pre-filling solution for CPB modeling. At 30 min before CPB (T1), immediately after left hilar opening (T2) and end of experiment (T3), the hemodynamic indexes, blood gas indexes, serum inflammatory factors, lung wet-day ratio and water content and lung tissue oxidative stress indexes were determined. Results: At T2 and T3, compared with CPB group, in PHC group the heart rate and mean arterial pressure increased significantly, the oxygenation index increased significantly, the respiratory index decreased significantly, and the lung wet-day ratio and water content decreased significantly. At T3, compared with CPB group, in PHC groups the serum tumor necrosis factor a, interleukin 6 and interleukin 1 beta levels decreased significantly, the lung tissue superoxide dismutase level increased significantly, and the myeloperoxidase and malondialdehyde levels decreased significantly. Conclusions: PHC treatment can alleviate the CPB-related lung injury in rats. The mechanisms may be related to its reducing inflammatory response and resisting oxidative stress.