Oxidative stress-induced cerebral ischemia is associated with the excessive generation of free radicals and their derivatives. Free radicals in moderate amounts are necessary to maintain redox homeostasis, whereas their aberrant production causes brain damage. Overexpression of superoxide dismutases, downregulation of nicotinamide adenine dinucleotide phosphate-oxidase and the activation of nuclear factor-E2-related factor 2 are some of the key endogenous anti-oxidant defense mechanisms that alleviate oxidative stress-induced brain injury. Furthermore, the administration of exogenous anti-oxidants such as resveratrol, allopurinol, omega-3 fatty acids, N-acetyl-l-cysteine, melatonin and ursolic acid repress multiple oxidative stress targets and consequently enhance endogenous anti-oxidant activity to provide post-ischemic neuroprotection. This chapter provides an insight into various neuroprotective strategies against oxidative stress-induced neuronal loss.