Tenascin-X (Tnxb) is a large extracellular matrix protein that has been associated with atherosclerosis. The objective of this study was to investigate the effect of Tnxb and its contribution to recovery after myocardial ischemia/reperfusion (I/R) injury. Tnxb expression was reduced in ECs of mice with ligation of the left anterior descending. Conditional Tnxb overexpression using adeno-associated viruses promoted Akt phosphorylation and mitigated myocardial injury and cardiac dysfunction in mice with myocardial I/R. Furthermore, overexpression of Tnxb alleviated apoptosis and enhanced angiogenesis in vivo and in vitro. Krueppel-like factor 4 (Klf4) recruited SWItch/sucrose nonfermentable (SWI/SNF) to the distal enhancer of Tnxb to transcriptionally activate Tnxb, thereby promoting Akt phosphorylation. The mitigating effect of Klf4 overexpression on I/R-induced endothelial apoptosis and angiogenic dysfunction was dependent on Tnxb activation, since Tnxb knockdown reversed the effects of Klf4 overexpression on myocardial I/R injury. In summary, we show that Klf4 recruits SWI/SNF to the distal enhancer of Tnxb to transcriptionally activate Tnxb, which promotes Akt phosphorylation and alleviates myocardial I/R-induced endothelial apoptosis and angiogenic dysfunction. Lastly, Tnxb was identified as a potential therapeutic target in EC injuries induced by myocardial I/R.