Abstract: AIM:To investigate the effects of TDZD-8, a GSK-3β inhibitor, on acute myocardial ischemia/reperfusion injury and to determine whether the protection is associated with the downregulation of NF-κB and the inhibition of inflammation. METHODS: Sixty healthy male Sprague Dawley rats were randomly divided into ischemia/reperfusion (I/R group), ischemia/reperfusion+drug group (I/R+D group), ischemia/reperfusion+vehicle group (I/R+V group) and sham group. Rats were subjected to 30 min ischemia followed by 3 h reperfusion. Myocardial infarct sizes were detected by TTC staining and myocardial tissue neutrophil infiltration. Changes in inflammatory factors were evaluated using HE staining and ELISA method. Phosphorylation of NF-κB and GSK-3β was measured by Western blotting. RESULTS: TDZD-8 reduced the infarct size and neutrophil infiltration (P<0.01) and inhibited NF-κB activation (P<0.01) and levels of cardiac-derived TNF-α and IL-6 (P<0.01). CONCLUSION: GSK-3β inhibitor, TDZD-8, can protect myocardial ischemia/reperfusion injury and may be related to the inhibition of NF-κB activation and the inhibition of inflammation.