The aim of this study was to investigate the effect of 17-methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) on nuclear factor-kappa-binding (NF-κB) 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-Triphenyltetrazolium chloride (TTC) staining. Levels of malondialdehyde, glutathione peroxidase, and total superoxide dismutase were assessed. Release of interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10) was measured by means of an enzyme-linked immunosorbent assay. NF-κBp65 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-1β and IL-6 levels, the expression of caspase-3, NF-κBp65, 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 MI/RI possibly by reducing lipid peroxidation damage while inhibiting the activity of NF-κBp65 and the inflammatory response.