Objective To compare the effects of mild hypothermia induced in different time courses on rats subjected to 3 hours (h) of ischemia followed by 3h or 72h of reperfusion. Methods Eighty male praue-Dawley rats were divided into three mild hypothermic (MHT, 32±0.2℃) groups, including intra-ischemia (MHTi), intra-reperfusion (MHTr), and intra-ischemia/reprefusion (MHTI+r) group, and one normothermic group (NT, 37±0.2℃) as the control. Reversible focal ischemia was carried out in rats with suture model. The cortical blood flow was measured during 3h of ischemia followed by 3h of reperfusion. The permeability of brain blood barrier (BBB) was estimated after 3h of reperfusion. The infarct volume was measured at 72h after reperfusion to determine the efects of MHT. Results The acute post-ischemic hyperperfusion and delayed hypoperfusion in ischemic perifocal region and sustained hypoperfusion in ischemic core were inhibited in MHTi+r and MHTi rats (P<0.05). MHTi+r protection on post-ischemic progressive hypoperfusion in the perifocal region was more effective than that MHTi (P<0.05). The BBB diruption and the infarct volume were significantly reduced in both MHTi and MHTi+r groups (P<0.05), especially in the MHTi+r rats. Conclusions This study demonstrates that MHTi+r has more substantial protective effects on reducing ischemia/reperfusion injury than MHTi. It may inhibit post-ischemic hyperperfusion and delayed or sustained hypoperfusion in ischemic perifocal regions, and reduce brain blood barrier disruption in the cortex region.