Drug-induced cardiotoxicity is a major concern during drug development, prompting the need for reliable experimental models to thoroughly assess potential cardioprotective drugs. The review delves into the intricacies of various models for drug-induced cardiotoxicity in experimental animals, with a specific focus on streptozotocin, isoprenaline, and antineoplastic drugs like cisplatin, doxorubicin, and 5-fluorouracil in rats and mice. Streptozotocin-induced cardiotoxicity is characterized by oxidative stress, inflammation, and mitochondrial dysfunction, resulting in myocardial damage and impaired cardiac function. Preclinical studies employing streptozotocin-induced cardiotoxicity models have revealed crucial pathways related to diabetic cardiomyopathy, aiding the evaluation of potential cardioprotective interventions. Isoprenaline, a beta-adrenergic agonist, is known for inducing acute myocardial injury resembling cardiac ischemia and heart failure in animals. Its mechanism involves overstimulation of beta-adrenergic receptors, calcium overload, oxidative stress, and apoptosis. Isoprenaline-induced models have offered insights into acute myocardial injury pathophysiology and facilitated the screening of cardioprotective agents against Myocardial Infarction (MI) and injury. Antineoplastic drugs, such as cisplatin, doxorubicin, and 5-fluorouracil, are linked to significant cardiotoxic effects, including cardiomyopathy and heart failure. Animal models have revealed dose-dependent cardiomyopathy, shedding light on underlying mechanisms like oxidative stress, Deoxyribonucleic Acid (DNA) damage, and mitochondrial dysfunction. The article aims to consolidate the current understanding of the pathophysiology and mechanisms behind drug-induced cardiac damage. Additionally, it underscores the importance of using animal models in preclinical evaluations to assess drug safety and efficacy and to develop potential cardioprotective therapies.