The aim of this study was to determine the effects of hesperidin (HP) on neuronal damage in brain tissue caused by global cerebral ischemia/reperfusion (I/R) in C57BL/J6 mice. For this purpose, a total of 40 mice were divided equally into four groups: (1) sham-operated (SH), (2) global cerebral I/R, (3) HP, and (4) HP+I/R. The SH group was used as a control. In the I/R group, the bilateral carotid arteries were clipped for 15 min, and the mice were treated with vehicle for 10 days. In the HP group, mice were administered HP (100 mg/kg) for 10 days without carotid occlusion. In the HP+I/R group, the I/R model was applied to the mice exactly as in the I/R group, and they were then treated with 100 mg/kg HP for 10 days. Cerebral I/R significantly induced oxidative stress via an increase in lipid peroxidation and a decrease in the components of the antioxidant defense system. Furthermore, cerebral I/R increased the incidence of histopathological damage and apoptosis in brain tissue. HP treatment significantly reversed the oxidative effects of I/R and inhibited the development of neurodegenerative histopathology. Therefore, the current study demonstrates that HP treatment effectively prevents oxidative and histological damage in the brain caused by global I/R. In this context, the beneficial effects of HP are likely a result of its strong antioxidant and free radical-scavenging properties. HP may be an useful treatment to attenuate the negative effects of global cerebral I/R.