Background: Ischemia-reperfusion brain injury (IRBI) is an important cause for mortality and morbidity. Studies on humans and animals showed that oxidative stress (OS) plays a crucial role in ischemic stroke with or without reperfusion. Allicin is reported to be able to attenuate OS and has neuroprotective effects on rabbits' ischemia-reperfusion spinal cord injury. Aim: To explore whether Allicin pretreatment has neuroprotective effects on IRBI in mice. Methods and results: Transient middle cerebral artery occlusion (MCAO) was conducted to induce IRBI in mice. The mice were pretreated with either Allicin (MCAOA) or normal saline in the same volume (MCAONS). Sham-operated groups [Allicin group (SOA) and normal saline group (SONS)] were also set. Blood pressure and cerebral blood flow measurements revealed comparable hemodynamics. Via brain MRI and neuronal nuclear antigen (NeuN) immune-histochemical staining, MCAOA mice had a significantly reduced stroke size than MCAONS mice (P < 0.05, n = 15). Allicin pretreatment could attenuate the OS, the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, inflammation, dysfunction of mitochondrial respiratory chain, and apoptosis (all P < 0.05, n = 15). Furthermore, Allicin also increased the activities of endogenous antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPX), and glutathione S-transferase (GST), and promoted the angiogenesis in the peri-infarct zone (all P < 0.05, n = 15). Conclusion: We showed that Allicin could protect mice from IRBI through a series of mechanisms. Allicin represents a new therapeutic direction of IRBI.