Objective To investigate the neuroprotective effects of low dose intravenous minocycline against ischemia reperfusion injury in rats after focal cerebral ischemia reperfusion and to explore the possible mechanism. Methods Seventy-two rats were randomly divided into sham-operated group(S group), cerebral ischemia/reperfusion group (I/R group), and minocycline intervention group (I/R+MC group). Focal cerebral ischemia was induced by filament medial cerebral artery occlusion method. Minocycline (3 mg/kg) in saline was administered intravenously via the caudal vein twice a day for 14 days in the I/R+MC group. At 2 days after ischemia reperfusion, the infarct volume was evaluated using TTC staining, the permeability of blood-brain barrier was assessed by Evan's blue (EB) dye extravasation, and the expressions of high mobility group box-1 protein (HMGB1) and Iba1, a marker of activated microglia, were analyzed by using Western blotting analysis. The neurological function recovery was evaluated using the modified neurological severity score (mNSS) at 2 d, 7 d, and 14 d after ischemia/reperfusion. Results Two days after cerebral ischemia reperfusion, the brain infarction volume and the extravasations of EB were significantly increased and the expressions of HMGB1 and Iba1 were significantly up-regulated in I/R group compared with sham group(P<0.05). Compared with I/R group, minocycline at 3 mg/kg via the caudal vein significantly reduced the infarct volume in ischemic brain(P<0.05), extravasation of EB and expressions of HMGB1 and Iba1 (P<0.05). Additionally, the rats in I/R+MC group exhibited a significantly decreased neurological severity score compared with I/R group (P<0.05). Conclusion Minocycline exerts a neuroprotective effect in rats with cerebral ischemia reperfusion injury, which may be related to decrease of infarct size, inhibition of EB extravasation and microglia activation.