Lithium is a renowned pharmacological treatment for mood disorders. Recent studies suggest that lithium chloride (LiCl) performs neuroprotective effects on cerebrovascular diseases. The present study is to investigate the protective effects of LiCl treatment on the hippocampus of mice with repeated cerebral ischemia-reperfusion (IR). Mice were subjected to IR through repeated bilateral common carotid artery occlusion. LiCl (2 mmol/kg) was administered daily postoperative until the mice were sacrificed. Swimming time was prolonged and error count increased in the model group through learning and memory tests. Pathological changes such as reduction in cell count and obvious pyknosis were seen in haematoxylin-eosin staining, and apoptosis was detected by TUNEL staining in hippocampal CA1 regions in the model group. The model animals exhibited more phospho-Akt Ser473 and phospho-GSK3β Ser9 than the sham group when measured by Western blot. LiCl treatment mitigated the prolonged swimming time and the increased error count compared with NaCl-treated group and improved the pathological changes. Meanwhile, LiCl further up-regulated phospho-Akt Ser473 and phospho-GSK3β Ser9 expression. The highest level of diversity was at 4 weeks postoperative. Therefore, repeated IR can severely damage the hippocampus and decrease the learning and memory functions in mice. Changes in the Akt and GSK3β protein activity were involved in the IR process. LiCl treatment exerted a neuroprotective effect on learning and memory by potentiating the Akt/GSK3β cell-signaling pathway.