Objective: To investigate the effect of hydrogen-rich saline (HRS) on lung injury secondary to severe acute pancreatitis (SAP) in rats and its association with NOX2/ROS/NF-κB pathway. Methods: Seventy-two male Wistar rats were equally randomized into sham operation group, SAP model group (SAP group) and SAP model plus HRS treatment group (HRS group). SAP model was induced by retrograde infusion of 5% sodium taurocholate into the biliopancreatic duct. Five minutes after operation, rats in HRS group underwent tail vein injection of HRS (6 mL/kg), while those in sham operation group and SAP group were given the same volume of normal saline instead. Rats were sacrificed in four batches with equal number of animals at 3, 12 and 24 h after operation. Then, in each group of rats, the pathological examinations of pancreatic and lung tissues were performed, the serum levels of pancreatic enzymes, the malondialdehyde(MDA) content and superoxide dismutase (SOD) activity, and the expressions of NOX2, NF-κB, and TNF-α in lung tissue were measured. Results: Compared with sham operation group, rats in either SAP group or HRS group exhibited manifestations of SAP and lung injury, as evidenced by significantly increased pathological scores of the pancreatic and lung tissues, elevated serum pancreatic enzyme levels and lung MDA content, and reduced lung SOD activity (all P<0.05); but all these injury parameters in HRS group, except the pancreatic enzyme levels (all P>0.05), were significantly lower than those in SAP group (all P<0.05). Results of the immunohistochemical staining at 12 h after operation showed that the expression levels of NOX2, NF-κB and TNF-α in lung tissue were significantly increased in both SAP group and HRS group compared with sham operation group (all P<0.05), while all those in HRS group were significantly lower in HRS group versus SAP group (all P<0.05). Conclusion: HRS can alleviate SAP-induced lung injury in rats, and the mechanism may be associated with inhibition of the activation of NOX2/ROS/NF-κB pathway.