BACKGROUND Renal ischemic-reperfusion (RIR) injury remains a major cause of acute kidney injury, with increased in-hospital mortality and risks for chronic kidney disease. Previous studies have proposed that oxidative stress, inflammation, and renal apoptosis are the most common causes of injury, whereas recent research proved that methane, the simplest alkane generated by an enteric microorganism or accompanying the production of reactive oxygen species (ROS), can alleviate inflammation and oxidative stress and reduce apoptosis in different organs. MATERIAL AND METHODS In the present study, we analyzed the possible effects of methane-rich saline in RIR injury in a mouse model and analyzed its possible protective effects on inflammation, oxidative stress, and apoptosis. RESULTS The results showed that treatment with methane significantly improved blood creatinine and blood urea nitrogen (BUN) levels and improved renal histology in RIR injury. Further experimentation proved that this protective effect was primarily manifested in decreased oxidative stress, less apoptosis, and reduced inflammation in renal tissues, as well as improved general responses. CONCLUSIONS Our present study proved the protective effects of methane in RIR injury and, together with previous research, confirmed the multi-organ protective effects. This may help to translate methane application and develop its use in organ ischemic-reperfusion injury.