Methane exerts neuroprotective effects on spinal cord ischemia-reperfusion injury. Methane activates Nrf2 in neurons, microglia and astrocytes in the spinal cord. The increased Nrf2 signaling inhibits oxidative stress and neuronal apoptosis. It also reduces proinflammatory response and blood-spinal cord barrier dysfunction. Our results elucidate Nrf2-dependent benefits of methane for spinal cord injury.