Objective To compare the effects of mild hypothermia induced in different time courses on rats subjected to 3 hours (h) of ischemia followed by 3 h or 72 h of reperfusion.Methods Eighty male Sprague-Dawley rats were divided into three mild hypothermic (MHT, 32±0.2℃) groups, including intra-ischemia (MHTi), intra-reperfusion (MHTr), and intra-ischemia/reperfusion (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 3 h of ischemia followed by 3 h of reperfusion. The permeability of brain blood barrier (BBB) was estimated after 3 h of reperfusion. The infarct volume was measured at 72 h after reperfusion to determine the effects 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 of MHTi (P<0.05). The BBB disruption 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.