Objective Cysteinyl leukotrienes are potent inflammatory mediators. Their actions are mediated by specific receptors, the CysLT receptors (CysLT1 R and CysLT2 R), which have been cloned and characterized. In this study, we investigated the protective effects of the CysLTR antagonist Pranlukast and HAMI 3379 on global cerebral ischemia/reperfusion (CI/ R) injury in gerbils and its underlying mechanisms. Methods The gerbil model of CI/ R was established by bilateral common carotid artery occlusion for 10 min followed by 24 h reperfusion. Then the animals were equally randomized into four groups: sham, model, Pranlukast (0.1 mg/ kg) and HAMI 3379 (0.1 mg/ kg)groups. The later two groups were treated with intraperitoneal injection of Pranlukast and HAMI 3379,respectively,once daily for 4 days before carotid artery occlusion, while the former two groups with saline only, all at 10 mL/ kg. After 24 h reperfusion, neurological deficit scores were observed and the behavioral dysfunction was assessed. The neuron morphology of cerebral cortex and CA1 subregion of hippocampus were observed in brain sections stained with cresyl violet. The expression of autophagy-related proteins beclin-1 and LC3 in the homogenate of cerebral cortex and hippocampus were determined using western blottingm analysis. The ultrastructure of autophagosomes in the CA1 subregion of hippocampus was observed by electron microscopy. Results Compared with the model group, Pranlukast and HAMI 3379 attenuated neurological deficits, improved the behavioral dysfunction, inhibited the neuron injury and loss, decreased the expression of autophagy-related protein beclin-1 and LC3 and the number of autophagosomes. Conclusions cysteinyl Leukotriene receptor antagonist Pranlukast and HAMI 3379 can alleviate global cerebral ischemia/ reperfusion injury in gerbils. The protective effects of Pranlukast and HAMI3379 appear to be associated with the inhibition of autophagy.