The aim of the present investigation was to assess neuroprotection exerted by GABA (100 nM-100 mM) in rat cortical brain slices subjected to oxygen-glucose deprivation and reoxygenation. Neuronal injury and neuroprotection were assessed by measuring the release of glutamate and lactate dehydrogenase and tissue water content. Results demonstrate that GABA exerted neuroprotective effects according to a U-shaped, hormetic-like, concentration-response curve, with an efficacy window of 10-100 μM concentration. In order to verify whether GABA-neuroprotective effects were GABAAor GABAB-mediated, Muscimol (GABAA agonist) and Baclofen (GABAB agonist) were tested. Results demonstrated that only Muscimol exerted neuroprotection according to a U-shaped, hormetic-like, concentration-response curve, while baclofen was ineffective. In conclusion, the hormetic response of GABA or GABAA agonists should be taken into consideration when designing experiments aimed at assessing neuroprotection by these agents against ischemia/reoxygenation injury.