Reperfusion therapy after cerebral ischemia often leads to reperfusion injury which may cause brain edema and blood-brain barrier (BBB) dysfunction. As a natural bioflavonoid, quercetin may exert protective effects on BBB dysfunction. This study aimed to investigate effects of quercetin in a rat model of global cerebral ischemia reperfusion (I/R) injury and explore the potential mechanism. Male rats were randomly divided into 4 groups: sham group, I/R group, quercetin-treated group (25 μmol/kg twice daily for 3 consecutive days before I/R), and quercetin/DKK-1-treated group. Global cerebral I/R was induced by bilateral common carotid artery occlusion combined with hypotension for 20 min and reperfusion for 24 h. Neurological function was scored, and then rats were sacrificed. The brain was harvested for HE staining, NeuN staining, and detection of brain water content. The BBB structure and permeability were examined by transmission electron microscopy and Evans blue extravasation, respectively. The protein expression of MMP-9, ZO-1, Claudin-5, β-catenin, and GSK-3β, and the mRNA expression of Axin and LEF1 were detected in either the absence or presence of Wnt/β-catenin inhibitor DKK-1. Results showed that quercetin reduced brain edema and BBB leakage, and improved BBB dysfunction. Quercetin could increase the expression of ZO-1, Claudin-5, β-catenin, and LEF1, and decrease the expression of MMP-9, GSK-3β and Axin. And all these protective effects of quercetin could be reversed by DKK-1. Thus, quercetin can alleviate BBB dysfunction after global cerebral I/R in rats and the mechanism may be related to the activation of canonical Wnt/β-catenin signaling pathway.