We have previously shown that melatonin reduces infarct volumes and enhances neurobehavioral and electrophysiological recoveries following transient middle cerebral artery (MCA) occlusion in rats. In the study, we examined whether melatonin would display neuroprotection against neuronal, axonal and oligodendrocyte pathology after 24 hr of reperfusion following 1 hr of MCA occlusion in mice. Melatonin (5 mg/kg) or vehicle was given intraperitoneally at the commencement of reperfusion. Neurological deficits were assessed 24 hr after ischemia. Gray matter damage was evaluated by quantitative histopathology. Axonal damage was determined with amyloid precursor protein and microtubule‐associated protein tau‐1 immunohistochemistry to identify postischemic disrupted axonal flow and oligodendrocyte pathology, respectively. Oxidative damage was assessed by 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) and 4‐hydroxynonenal (4‐HNE) immunohistochemistry. Relative to controls, melatonin‐treated animals not only had a significantly reduced volume of gray matter infarction by 42% (P < 0.001), but also exhibited a decreased score of axonal damage by 42% (P < 0.001) and a reduction in the volume of oligodendrocyte pathology by 58% (P < 0.005). Melatonin‐treated animals also had significantly reduced immunopositive reactions for 8‐OHdG and 4‐HNE by 53% (P < 0.001) and 49% (P < 0.001), respectively. In addition, melatonin improved sensory and motor neurobehavioral outcomes by 47 and 30%, respectively (P < 0.01). Thus, delayed (1 hr) treatment with melatonin reduced both gray and white matter damage and improved neurobehavioral outcomes following transient focal cerebral ischemia in mice. The finding of reduced oxidative damage observed with melatonin suggests that its major mechanisms of action are mediated through its antioxidant and radical scavenging activity.