Objective To investigate the protective effects and mechanisms of action of rhodanine against cerebral ischemia-reperfusion injury. Methods A rat model of middle cerebral artery occlusion (MCAO) was created by exposure to ischemia for 2 h and reperfusion for 24 h. Neuroprotective score and cerebral infarction volume were used to evaluate the protective effects of rhodanine against cerebral ischemia-reperfusion injury. The superoxide dismutase (SOD) activity,the activity of glutathione peroxidase (GSH-Px) and the level of malondialdehyde (MDA) were detected. The expression of Bax, Bcl-2, and caspase-3 proteins were explored to reveal the brain-protective mechanism. Results Compared with those in the model group, the neurobehavioral scores and cerebral infarction volume ratios of the groups with low, medium, and high dose rhodanine were significantly lower ( P <0. 05). Compared with those in the model group, the activity levels of SOD and glutathione peroxidase (GSH-Px) in brain tissue were significantly increased in the groups with low, medium,and high dose rhodanine, while their malondialdehyde (MDA) levels were significantly decreased ( P < 0. 05). The expression levels of Bax and caspase-3 were decreased and the expression of Bcl-2 protein was increased in the low-,medium-, and high-dose groups. Conclusions Rhodanine has protective effects against cerebral ischemia-reperfusion injury, and its mechanism may be related to the improvement of SOD and GSH-Px activity, the decrease of MDA level, and an antioxidative effect. Upregulation of Bcl-2 protein expression and downregulation of Bax and caspase-3 protein expression may also be involved, indicating a relationship with neuronal apoptosis.