Cerebral ischemia causes tissue death owing to occlusion of the cerebral blood vessels, and cerebral ischemia activates mitogen-activated protein kinase (MAPK) and induces secretion of pro-inflammatory cytokines. Adenosine A2A receptor agonist, polydeoxyribonucleotide (PDRN), suppresses the secretion of pro-inflammatory cytokines and exhibits anti-inflammatory effect. In the current study, the therapeutic effect of PDRN on cerebral ischemia was evaluated using gerbils. For the induction of cerebral ischemia, the common carotid arteries were exposed, and then aneurysm clips were used to occlude the common carotid arteries bilaterally for 7 minutes. In the PDRN-treated groups, the gerbils were injected intraperitoneally with 0.3 mL of saline containing 8 mg/kg PDRN, per a day for 7 days following cerebral ischemia induction. In order to confirm the participation of the adenosine A2A receptor in the effects mediated by PDRN, 8 mg/kg 7-dimethyl-1-propargylxanthine (DMPX), adenosine A2A receptor antagonist, was treated with PDRN. In the current study, induction of ischemia enhanced the levels of pro-inflammatory cytokines and increased phosphorylation of MAPK signaling factors in the hippocampus and basolateral amygdala. However, treatment with PDRN ameliorated short-term memory impairment by suppressing the production of pro-inflammatory cytokines and inactivation of MAPK signaling factors in cerebral ischemia. Furthermore, PDRN treatment enhanced the concentration of cyclic adenosine-3,5'-monophosphate (cAMP) as well as phosphorylation of cAMP response element-binding protein (p-CREB). Co-treatment of DMPX and PDRN attenuated the therapeutic effect of PDRN on cerebral ischemia. Based on these findings, PDRN may be developed as the primary treatment in cerebral ischemia.