The aim of this study was to investigate the effect of 17-methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) on nuclear factor-kappa-binding (NF-kappa B) and the inflammatory response in rats with myocardial ischemia reperfusion injury (MI/RI). Sprague Dawley rats were randomly divided into 7 groups, and the rat MI/RI model was established by the ligation of the left anterior descending for 30 minutes followed by ligation release for 1 hour. Areas of myocardial infarction were measured using Evans blue-2,3,5-Triphenyhetrazolium chloride (TTC) staining. Levels of malondialdehyde, glutathione peroxidase, and total superoxide dismutase were assessed. Release of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and interleukin-10 (IL-10) was measured by means of an enzyme-linked immunosorbent assay. NF-kappa Bp65 and intercellular adhesion molecule-1 protein expression and caspase-3 and adenine nucleotide translocator-1 messenger RNA expression were evaluated by immunohistochemistry and reverse transcription polymerase chain reaction, respectively. Pretreatment with MHBFC decreased the infarction areas, the malondialdehyde, IL-1 beta and IL-6 levels, the expression of caspase-3, NF-kappa Bp65, and intercellular adhesion molecule-1. Further, MHBFC increased total superoxide dismutase and glutathione peroxidase activities, the release of IL-10, and the expression of adenine nucleotide translocator-1 messenger RNA compared with the results of the model group. The experiment showed that MHBFC protected the heart against MITRI possibly by reducing lipid peroxidation damage while inhibiting the activity of NF-kappa Bp65 and the inflammatory response.