Theanine and caffeine, 2 naturally occurring components in tea, have repeatedly been shown to deliver unique cognitive benefits when consumed in combination. In this study, we assessed the beneficial synergistic effects of concurrent treatment with theanine and caffeine against cerebral damage in rats. Theanine and caffeine had no effect on physiological variables, including pH, partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2), mean arterial blood pressure, plasma glucose, or regional cerebral blood flow. Treatment with theanine (1 mg/kg body mass, intraperitoneal injection) alone significantly reduced cerebral infarction induced by cerebral ischemia-reperfusion, but caffeine (10 mg/kg, intravenous administration) alone only had a marginal effect. However, the combination of theanine plus caffeine resulted in a significant reduction of cerebral infarction and brain edema compared with theanine monotherapy. Meanwhile, increased malondialdehyde levels as well as decreased superoxide dismutase activity, glutathione peroxidase activity, and glutathione levels observed in the cerebral cortex after cerebral ischemia-reperfusion were significantly ameliorated by the combination therapy. Furthermore, the elevated inflammatory response levels observed in the cortex after cerebral ischemia-reperfusion were markedly attenuated by the combined treatment. Thus, it is suggested that the neuroprotective potential of a combination therapy with theanine and caffeine against cerebral ischemia-reperfusion is partly ascribed to their antioxidant and anti-inflammatory properties.