Introduction: Cardiotoxicity is an important side effect of the treatment of a malignant tumour with Anthracyclines. The anthracycline family drug epirubicin (EPI) is one of the most potent chemotherapeutic agents for treating a range of solid and hematologic malignant tumours. However, its anti-tumor efficacy is dose-dependent, and the development of cardiac-toxicities limits its clinical use. In various Pharmacological Studies Roflumilast (ROF), a PDE-4 Inhibitor has been shown a Neuroprotective and Cardioprotective response but its role in EPI-induced cardiotoxicity and the underlying mechanisms has never been Evaluated. Hypothesis: The Study hypothesized that Roflumilast exerts cardioprotection against EPI-induced cardiotoxicity through attenuating cardiac mitochondrial dysfunction and inflammatory markers. Methods: Wistar rats of either sex were employed into 4 groups 3 groups comprised 7 animals while the control group had 5 animals, EPI-treated rats were intraperitoneally injected with 10 mg/kg for 1 day, while control rats were on normal diet. EPI+ROF (Low Dose) treated rats were intraperitoneally injected with 10 mg/kg of EPI for 1 day and 1mg/kg of ROF via oral gavage for 7 days. While in the higher dose of EPI+ROF treated rats were intraperitoneally injected with 10 mg/kg of EPI for 1 day and 2mg/kg of ROF via oral gavage for 7 days. The rat hearts were rapidly removed to determine cardiac mitochondrial functions and various cardiac biomarkers. Results: EPI induced significantly excessive mitochondrial Oxidative Stress, increased tissue TBARS and decreased levels of SOD and GSH. Conversely, a 7-day treatment with ROF (1mg/kg/day , p.o .) and ROF (2mg/kg/day, p.o .) significantly reduced TBARS levels while increasing SOD and GSH concentrations. The levels of TNF-α, CK-MB AST, ALT, and LDH were noted to be markedly increased in EPI-induced rats. While treatment with ROF (1mg/kg/day, p.o., 7 days ) and ROF (2mg/kg/day, p.o., 7 days) showed significantly decreased levels of TNF-α, CK-MB AST, ALT, LDH. Conclusion: In the current investigation, it can be concluded that administration of EPI leads to Oxidative Stress, Inflammation and Cardiotoxicity. Treatment with the ROF 2mg/kg showed cardioprotective potential by significantly decreasing inflammatory markers, oxidative stress parameters and cardiotoxic parameters. Our findings suggest that ROF protects the heart from EPI-induced cardiotoxicity, and it may serve as a guide for future cardioprotective research strategies.