Our previous study showed that CD151 promotes neovascularization and improves blood perfusion in a rat hindlimb ischemia model. In this study, we investigated whether CD151 promotes neovascularization and improves ventricular function after myocardial infarction in rats and the mechanisms involved. Rats were subjected to sham surgery or coronary artery ligation. We used rAAV for direct delivery of the human CD151 gene into the rat myocardium. At 4 weeks after coronary artery ligation, human CD151 mRNA was detected using RT-PCR. Measurement of capillary density was evaluated using immunostaining for von Willebrand factor, and hemodynamic variables and physiological parameters were monitored. Western blot analysis for CD151, PI3K, phosphor-Akt, total Akt, phosphor-eNOS, and total eNOS was performed. In addition, we also observed the effect of CD151 on the expression of VEGF using Western blot analysis. CD151 gene delivery could increase the expression of CD151 at gene and protein levels. Overexpression of CD151 could increase the number of microvessels in the ischemic myocardium and significantly improved the hemodynamic variables after myocardial infarction. In addition, CD151 could activate the PI3K pathway, including activation of Akt and eNOS, but did not affect the expression of VEGF. This study suggested that CD151 could promote neovascularization and improve ventricular function after myocardial infarction in rats. The mechanism may be that CD151 can activate the PI3K pathway and promote neovascularization via the PI3K pathway, without affecting ischemia-induced VEGF expression.