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Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide, and both cardiac necroptosis and endoplasmic reticulum stress (ERS) have been involved in the pathophysiology of AMI. ZYZ‐803 is a hybrid molecule of a dual donor for gasotransmitters H₂S and NO. The aim of the present study is to investigate the antinecroptosis role and potential mechanisms of ZYZ‐803 in the setting of ERS during AMI injury. In vivo, ZYZ‐803 preserves cardiac function and reduces infarct size significantly after 24‐hour left coronary artery ligation through revising H₂S and NO imbalance. In addition, ZYZ‐803 relieves ERS and necroptosis in an AMI heart. In vitro, ZYZ‐803 ameliorates ERS‐related necroptosis induced by tunicamycin, and such effect has been depending on the receptor‐interacting protein 3‐ (RIP3‐) Ca²⁺‐calmodulin‐dependent protein kinase (CaMKII) signaling pathway. These …