Objective To investigate the effects of dezocine on β2-adrenergic receptor (β2AR)/β-arrestin2/nuclear factor-κB (NF-κB) pathway and myocardial apoptosis in rats with myocardial ischemia-reperfusion injury. Methods Sixty rats were randomly divided into sham operation group (Sham group), myocardial ischemia reperfusion injury model group (MIRI group), high , medium and low dose dezocine groups (20,10,5mg/kg), with twelve rats in each group. 30 minutes before modeling, each treatment group was injected with the corresponding dose of dezocine via femoral vein, and the Sham group and MIRI group were given the same amount of normal saline. Except for the sham operation group, the other groups were given the method of surgical ligation of the left anterior descending coronary artery to establish a rat MIRI model. After 2 hours of reperfusion, the heart rate (HR), left ventricular systolic pressure (LVSP) and left ventricular end diastolic (LVEDP) of rats were measured to evaluate cardiac function. The serum levels of creatine kinase (CK), creatine kinase isoenzyme MB (CKMB), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were detected. The histological changes of left ventricle were observed by hematoxylin eosin (HE) staining. The apoptosis of myocardial cells were observed and the apoptosis index was calculated by TUNEL staining. The protein expression of Bcl-2, Bax, and caspase-3 was detected by immunohistochemistry. The protein expression of β2AR, β-arrestin2, IκBα, and NF-κB p65 was detected by Western blot. Results Myocardial histopathology showed that the myocardial fibers in Sham group were complete and arranged neatly, while the myocardium in MIRI group was seriously damaged. The local muscle fibers disappeared and a large number of inflammatory cells infiltrated. Compared with Sham group, each treatment group improved obviously. Compared with Sham group, the HR, LVSP, Bcl-2/Bax ratio, protein expression of β2AR, β-arrestin2, IκBα in myocardial tissues in MIRI group were significantly lower (P＜0.05), and those in each treatment group were significantly higher than those in the MIRI group (P＜0.05). Compared with Sham group, the LVEDP, levels of CK, CK-MB, TNF-α, IL-6 in serum, protein expression of Bcl-2, Bax, Caspase-3, NF-κB p65 in myocardial tissues and myocardial cell apoptosis rate in MIRI group were significantly higher (P＜0.05), and those in each treatment group were significantly lower than those in the MIRI group (P＜0.05). Conclusion Dezocine can inhibit the inflammatory reaction, reduce the apoptosis of myocardial cells, and has a protective effect on MIRI rats. Its mechanism may be related to up regulating the expression of β2AR, β-arrestin2, and IκBα, and decreasing the expression of NF-κB p65.