Myocardial Ischemia/Reperfusion (MI/R) injury is a clinical phenomenon including myocardial structural damage, dysfunction and disorders of metabolism and electrophysiology after re-perfusion of ischemic heart tissues. It mainly occurs after myocardial infarction and by-pass surgery, and is one major issue in clinic. Lycopene has been known to exert anti-oxidation effects. This study thus investigated the protective role and possible mechanism of lycopene on rat MI/R injury. 80 male SD rats were randomly and equally divided into sham, MI/R, lycopene treatment, and lycopene+EX527 group (N=20). MI/R model was established by the ligation of left descending coronary artery for 30 min followed by reperfusion for 6 h. Ultrasonic cardiogram was used to evaluate cardiac functions, while serum enzyme and myocardial apoptosis were detected by ELISA and TUNEL assays respectively. The area of infarction was determined by Evans blue-TTC double staining. Western blot was used to detect the levels of Sirt1, cIAP1, Bax and Bcl-xl. Lycopene significantly improved cardiac functions as shown by lower CK and LDH levels. It can also decrease the infarction area and reduce apoptotic cell numbers. Sir1 and Bcl-xl expressions were up-regulated while cIAP1 and Bax were down-regulated after lycopene treatment. However, EX527, an inhibitor of Sirt1, can reverse such effects of lycopene (p<0.05 in all cases). Lycopene can protect rat cardiomyocytes from MI/R injury, possibly via activation of Sirt1 signaling pathway to decrease reactive stress response after MI/R injury and subsequent amelioration of inflammatory injury.