Objective To investigate the effect of yulangsan chalcone (YLSC) on the nuclear factor (NF)-κB signaling pathway in rats with myocardial ischemia / reperfusion injury (MI/ RI). Methods A rat model of MI/ RI was prepared by ligating the left anterior descending branch of the coronary artery. The extent of myocardial infarction was observed by double staining with Evans blue / TTC, and the serum concentrations of creatinine kinase (CK), CK-MB isoenzyme, and hydroxyproline were detected. Immunohistochemistry and western blot analyses were used to detect the protein expressions of NF-κB-inducing kinase (NIK), inhibitor of κB ( IκB), IκB kinase ( IκK) and NF-κB. Results YLSC reduced the extent of myocardial infarction in rats with MI/ RI; reduced the concentrations of CK, CK-MB isoenzyme, and hydroxyproline; inhibited the protein expressions of NIK, IκK and NF-κB; suppressed the enzyme activity of NIK and IκK; lessened the degradation of IκB and increased its expression. Conclusions YLSC exhibited protective effects in MI/ RI rats. The protective mechanism of YLSC may be related to a reduction in the extent of myocardial infarction, decrease in myocardial enzyme leakage, regulation of NIK/ IκK/ IκB/ NF-κB expressions in the inflammatory pathway, and reduction of the inflammatory response.