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Chloroquine, a prototype anti-malaria drug, has been reported to possess anti-inflammatory effects. Moreover, chloroquine pretreatment could improve DNA damage repair. It is therefore reasonable to hypothesize that chloroquine pretreatment could attenuate ischemia/reperfusion injury in the brain. Considering the fact that chloroquine could also improve glucose metabolism, we speculated that the potential effects of chloroquine on ischemia/reperfusion injury might be particularly pronounced in diabetic mice. In this study, chloroquine pretreatment protected neurons from Oxygen Glucose Deprivation (OGD) induced cytotoxicity and apoptosis. In vivo, Ob/ob mice and wildtype (WT) mice were pretreated with chloroquine for 3 weeks. Then, ischemic stroke was induced by 60 min Middle Cerebral Artery Occlusion (MCAO). We found that chloroquine pretreatment normalized blood glucose in diabetic ob/ob mice, and reduced cerebral damage after ischemic stroke especially for diabetic mice. In addition, chloroquine pretreatment reduced High-mobility group box 1 (HMGB1) content in the cerebrospinal fluid (CSF) and serum and lowered myeloperoxidase (MPO) activity and inflammatory cytokines gene expression both in the ob/ob diabetic mice and WT mice. Moreover, harmful DNA damage-signaling responses, including PARP activation and p53 activation, were also attenuated by chloroquine pretreatment in these two kinds of mice. In conclusion, chloroquine pretreatment could reduce cerebral damage after ischemic stroke especially in diabetic mice through multiple mechanisms, which include reducing neural cell DNA injury, restoring euglycemia and anti-inflammatory effects. The findings may provide potential for the development of chloroquine in the prevention and treatment of stroke in diabetic high-risk patients.