Objective To observe the protective effects of velvet antler peptide (VAP) on myocardial infarction (MI) ischemia and fibrosis injury in rats after coronary artery ligation and the mechanism of TGF-β/ Smad signaling pathway mediation by VAP. Methods 60 SPF male Wistar rats were randomly divided into six groups: Sham operation ;MI; positive drug control ( captopril, 30 mg / kg); low-, medium-, and high-dose ( 100, 200, and 300 mg / kg) VAP groups. The left anterior descending limb of the coronary artery was ligated to provide a model of myocardial injury in rats.Three days after the model was made, the rats were orally administered with 1 mL/ d VAP for 28 days. Two hours after the last administration, we collected blood aseptically from the abdominal aorta of anesthetized rats and centrifuged the samples to obtain VAP serum. Electrocardiogram was used to analyze the degree of myocardial injury. HE staining was used to observe pathological changes in the myocardial tissue of rats. Serum creatine kinase isoenzyme ( CK-MB) and cardiac troponin (cTn) levels were measured by enzyme linked immunosorbent assay ELISA. The levels of TGF-β1, Smad2 / 3, pSmad2 / 3, Smad4, Smad7, Collagen I and Collagen Ⅲ proteins in myocardial tissue were detected by Western blot. Results HE staining in the MI group showed that myocardial fibers group were disordered; transverse stripes had disappeared; cells were swollen, cracked, and necrotic; and nuclei were deformed and displaced compared with the findings in the Sham group. The pathological morphology of myocardium in KTPL group and VAP group was significantly improved compared with that in the MI group. ELISA showed significantly higher CK-MB, cTnT (cardiac troponin T), and cTnI (cardiac troponin I) levels in the MI group compared with the findings in the Sham group (P<0. 01). There were significantly lower CK-MB, cTnT, and cTnI contents in the myocardial tissue of positive drug control group KTPL and VAP groups compared with the findings in the MI group (P<0. 01). The Western blot showed that myocardial injury was caused by the up-regulation of TGF-β1, Smad2 / 3, p-Smad2 / 3, Smad4, Collagen I and Collagen Ⅲ and down-regulation of Smad7 protein expression in the MI group (P<0. 01). Compared with the findings in the Sham group. The expression of TGF-β1, Smad2 / 3, p-Smad2 / 3, Smad4, Collagen I and Collagen Ⅲ were significantly down-regulated and Smad7 was up-regulated in the KTPL group and VAP group, which improved fibrosis (P< 0. 01). Conclusions MI rats activate TGF-β/ Smad signal transduction, and captopril and VAP inhibit TGF-β1 and Smad proteins to improve myocardial fibrosis after MI. VAP may protect against myocardial ischemia and fibrosis after MI by regulating the TGF-β/ Smad signaling pathway.