Objectives: This study sought to elucidate the therapeutic mechanism of intravenous immunoglobulin (IVIG) in a mouse model of Kawasaki disease (KD) by evaluating changes in the expression and activity of NF-κB and MMP-9. Methods: Seventy-two C57BL/6 mice were divided into IVIG group, KD model group, and Control group. KD was induced in the IVIG and KD model groups by intraperitoneal (i.p) injection of Lactobacillus casei cell wall extract. The IVIG group was treated with an i.p injection of IVIG (2mg/g), while the KD model and control groups were treated with i.p injection of phosphate buffered solution. Coronary artery diameter was measured by echocardiography. H&E and elastic fiber staining were performed to observe pathological damage of the coronary artery. In cardiac tissue samples, NF-κB and MMP-9 expression were evaluated by western blotting, NF-κB DNA-binding activity was analyzed by electrophoretic mobility shift assay, and MMP-9 enzyme activity was assessed by gelatin zymography. Results: In the KD model group, focal inflammatory infiltrate of the coronary artery trunk and branches was evident on Days 14 and 28 of the experiment. Destrucion of coronary artery wall elastin was observed on Day 56. The average diameter of the left coronary artery in the IVIG group was significantly lower than that in the KD model group but higher than the Control group (Day 28: 0.41±0.03 vs. 0.48±0.07 and 0.35±0.02 mm; P<0.01). NF-κB and MMP-9 expression were sharply increased in the KD model group compared to the Control group (Day 28, NF-κB: 57.64±13.69 vs. 18.97±10.67 μg/L; MMP-9: 100.44±41.04 vs. 34.68±18.91 μg/L: all P<0.01). And the expression of NF-κB and MMP-9 in the IVIG group was obviously lower than the KD model group (Day 28, NF-κB: 24.62±13.58 vs. 57.64±13.69 μg/L; MMP-9: 38.76±19.25μg/L vs. 100.44±41.04 all P<0.01). NF-κB DNA-binding activity and MMP-9 enzyme activity were significantly increased in the KD model group compared to the Control group (Day 28, NF-κB DNA-binding activity: 84.78±20.81 vs. 27.22±4.99 μg/mL, P<0.01; MMP-9 enzyme activity 18,559.76±7,963.28 vs. 9,112.39±3,397.67μg/L, P<0.05). And the activity in the IVIG group was obviously lower than the KD model group (Day 28, NF-κB DNA-binding activity: 50.19±15.86 vs. 84.78±20.81μg/mL, P<0.01; MMP-9 enzyme activity 11834.28±4995.75 vs. 18,559.76±7,963.28μg/L P<0.05). Conclusions: NF-κB and MMP-9 are over-expressed and active in cardiac tissue of KD mice. IVIG suppresses inflammatory cell infiltration and prevents coronary artery lesions in the KD mouse model. The therapeutic effect of IVIG may have been achieved by suppression of the over-expression and increased activity of the NF-κB/MMP-9 pathway.