BACKGROUND: The use of tourniquets (TQ) during the total knee arthroplasty (TKA) induced ischemia-reperfusion (I/R) injury in the limb, resulting in the release of inflammatory cytokines and reactive oxygen species (ROS), therefore leading to myocardial damage. This study aimed to investigate the effects and molecular mechanism of Esketamine on myocardial injury (MI) caused by TQ-induced I/R injury. METHODS: A randomized numerical table method was used to divide 23 patients into the C group (11 cases, ACB + conventional anesthesia) and M group (12 cases, ACB + conventional anesthesia + 0.5 mg/kg Esketamine). The levels of lactate dehydrogenase (LDH), Malondialdehyde (MDA), Fe RESULTS: Compared with the C group, the levels of GSH-Px and GSH were increased while the levels of IL-6, TNF-α, MDA, Fe CONCLUSION: Esketamine alleviated cardiomyocyte ferroptosis via STING, which might be the molecular mechanism of Esketamine to ameliorate the MI caused by TQ-induced I/R injury. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10616-025-00723-9.