Tigecycline (TIG) toxicity is a threat to health because of the mortality risk attributed with its overdose. Large doses result in fatal cardiomyopathy and acute cardiotoxicity. Gentamicin (GEN) is an aminoglycosidal antibacterial agent that affects kidney function and is then reabsorbed by renal tubules, causing nephrotoxicity. Six groups of rats (n=5) were used. Control (DW), TIG 7, TIG14, GEN, TIG 7+ GEN, and TIG 14+ GEN groups. Cardiac catalase (CAT) activity, glutathione (GSH), and malondialdehyde (MDA) levels in the heart, as well as histopathological and immunohistochemical changes were recorded. Oxidative stress may be a common factor in the heart toxicity produced on by these substances. Ultrastructurally; myocardium from TIG 14+ GEN group exhibited typical changes for myocardial apoptosis and degeneration. Substantial variations in PCNA expression in cardiomyocytes, as well as an increase in interleukin-6 (IL-6) and annexin-V levels, especially in the TIG 14+ GEN group. GEN, in addition to its nephrotoxicity, increases TIG-induced cardiotoxicity. We intend to review the underlying mechanisms in cardiac lesions caused by TIG, with a particular emphasis on oxidative stress-related pathways. The biomarkers of oxidative stress may be beneficial in identifying cardiotoxicity earlier than usual after treatment with these prescription medications and may aid in the prevention of cardiac irreversible incidents.