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Hypoxia‐induced apoptosis is linked to the pathogenesis of myocardial infarction (MI) and heart failure. Ubiquitin‐specific peptidase 7 (USP7) is related to catabolic/pro‐apoptotic signaling. However, its role in cardiomyocyte injury is unclear. In this study, we aimed to investigate the role and the underlying regulatory mechanism of USP7 in MI. H9c2 cardiomyocytes were cultured in hypoxia to establish an in vitro model of myocardial hypoxic/ischemic injury. Sprague‐Dawley (SD) rats were used to establish animal models with MI. Quantitative real‐time polymerase chain reaction (qRT‐PCR) and Western blot assays were performed to evaluate the expression levels of miR‐409‐5p, USP7, and p53, respectively. After USP7 and miR‐409‐5p were selectively regulated in H9c2 cells, the inflammatory response, apoptosis, and cell viability were detected by ELISA, flow cytometry, and MTT assay, respectively. The interaction between USP7 and miR‐409‐5p was determined by bioinformatics analysis, qRT‐PCR, Western blot, and dual‐luciferase reporter assay. LVEF, LVIDd, and LVIDs of rats after MI were also measured. USP7 expression was markedly elevated while miR‐409‐5p expression was significantly down‐regulated in H9c2 cells under hypoxic culture. Augmentation of USP7 expression led to a dramatic promotion of hypoxia‐induced apoptosis of cardiomyocytes, accompanied by an increase in the secretion of the cytokines IL‐1β, TNF‐α, and IL‐6. Myocardial injury markers LDH, cTnI, and CK‐MB expressions were also increased. Besides, overexpression of USP7 aggravated left ventricular remodeling and decreased left ventricular function of the rats. Conversely, the up‐regulation of miR‐409‐5p expression protected H9c2 cells from apoptosis and inhibited the release of cytokines and myocardial injury. Left ventricular remodeling and left ventricular function were also improved by miR‐409‐5p overexpression. Furthermore, USP7 was identified as a target of miR‐409‐5p and the overexpression of miR‐409‐5p reversed the effects of USP7 on H9c2 cells. USP7 exacerbates myocardial ischemic injury by promoting inflammation and apoptosis of cardiomyocytes, and the up‐regulation of its expression is partly caused by the down‐regulation of miR‐409‐5p expression. [ABSTRACT FROM AUTHOR]