Our research team analyzed the microRNA (miRNA)-197-3p involved in cardioprotection, and we demonstrated that the overexpression of miRNA-197-3p could be linked to a higher risk of cardiac damage. Recent research indicated that miRNA-197-3p inhibits the effector proteins of the anaesthetic preconditioning mechanism of halogenated drugs. In this scenario, we proposed to determine the role of miRNA-197-3p in cardiac injury and its effects on myocardial conditioning under halogenated exposure. Patients having myocardial revascularization surgery have increased heart damage due to postoperative miRNA-197-3p upregulation. Human cardiac myocytes (HCMs) were used in an in vitro hypoxia/reperfusion (H/R) model. The miRNA-197-3p-MIMIC was transfected into the HCMs. Three H/R-induced HCM groups were performed: negative MIMIC-control transfected, MIMIC transfected, and non-transfected. Each H/R cell group was exposed to Propofol (P), Sevoflurane (S), or non-exposed. Healthy cell cultures were the control group. ELISA assays were used to assess the Akt1 and p53 cell secretion capacity, and the Next Generation Sequencing assay was used to measure the differential expression of miRNA targets. : The secretion capacity of H/R-induced HCMs transfected with the MIMIC was higher under sevoflurane exposure regarding Akt-1 cytokine (I/R + S: 0.80 ± 0.06 ng/mL; I/R + P: 0.45 ± 0.28 ng/mL; > 0.05), and lower regarding p53 cytokine (I/R + S: 38.62 ± 6.93 ng/mL; I/R + P: 43.34 ± 15.20 ng/mL; > 0.05) compared to propofol. In addition, a significant gene overexpression of five miRNAs, in the sevoflurane group, was linked to cardioprotection: miRNA-29-3p, 24-3p, 21-3p, 532, and miRNA-335-5p. miRNA-197-3p inhibits the cardioprotection induced by halogenated exposure and can be considered a biomarker of cardiac damage. Additional research is required to validate our findings in other clinical settings.