Loss of oxygen delivery to the brain during cardiac arrest can promote significant brain injury. While prompt resuscitation is critical, the reintroduction of oxygen can potentiate injury by promoting reactive oxygen species (ROS) generation. While mitigating ROS damage may serve as a therapeutic avenue for cerebral reperfusion injury, traditional attempts to scavenge ROS have failed. This failure is thought to be due to inherent difficulties with delivery to the brain and sub-cellular targets within the early minutes of reflow. We found that specific infrared light (IRL) wavelengths penetrate the brain and reversibly reduce the activity of cytochrome c oxidase (CcO). Accordingly, we developed a non-pharmacologic therapy using specific IRL wavelengths to non-invasively modulate CcO and circumvent these delivery barriers. Our previous data shows that IRL wavelengths that reduce CcO activity also directly modulate mitochondrial respiratory rate and membrane potential, block mitochondrial ROS production, and limit neuronal death following oxygen-glucose deprivation. We hypothesized that these wavelengths could be used to inhibit ROS generation following resuscitation from cardiac arrest and thus, provide neuroprotection. IRL therapy was first evaluated for neuroprotection in the rat model of global brain ischemia (bilateral carotid occlusion and systemic hypotension - 8 minutes). Rats were randomly enrolled into IRL treatment groups, initiated immediately upon reperfusion. After 14 days, animals subjected to ischemia demonstrated an 86% loss of neurons in the CA1 hippocampus. Strikingly, for the IRL-treated animals, loss of neurons was significantly less, ranging from 17% with the best treatment to 35% with the least efficacious regimen (n=8-12, p<0.05) and preserved neurologic function, assessed by radial arm maze (n = 10, p<0.05). Finally, preliminary data from a swine model of cardiac arrest/resuscitation show a reduction in neurologic deficit score (0-150 scale 0=no deficit, 150=brain dead) with IRL treatment (Cardiac Arrest/Resuscitation = 112, Cardiac Arrest/Resuscitation + IRL treatment = 1: N = 4-6/group). These data demonstrate that IRL therapy may provide a novel strategy for the treatment of post-cardiac arrest brain injury.