Gastrodin is one of the foremost effective components of traditional Chinese medicine Gastrodia elata Bl., which has been widely used for anti-hypertension in China. However, the protection from myocardial apoptosis in hypertension of gastrodin has not been systematic studied. Our current study investigated the therapeutic effects and underlying mechanisms of gastrodin on cardiac protection in hypertensive mice. Treatment of gastrodin in Ang II-infused C57BL/6 mice significantly alleviated the increase of blood pressure, cardiac dysfunction, heart tibial ratio, and cardiac pathological changes. Kyoto Encyclopedia of Genes and Genomes pathway analyses applied in the data of RNA-sequencing by gastrodin treatment identified 697 up-regulated transcripts and 714 down-regulated transcripts, as well as 1105 enriched signaling pathways, which also revealed that apoptosis and PRDX2/p53 pathway were involved in the cardiac protection role of gastrodin. Consistently, gastrodin treatment significantly reduced the cell apoptosis in cardiac tissues of Ang II-infused mice and Ang II-stimulated H9c2 cells. In addition, gastrodin treatment significantly also decreased the Bax/Bcl-2 ratio on protein level, and down-regulated the protein levels of cleaved-caspase3, cleaved-caspase9, PRDX2 and p53 in both cardiac tissues and H9c2 cells stimulated with Ang II. In conclusion, gastrodin treatment exhibits cardiac protection by reducing myocardial apoptosis and suppressing PRDX2/p53 pathway activation in vitro and in vivo.