Introduction: Azithromycin, a widely used antibacterial agent, is also considered the cornerstone of the management protocols for COVID-19 infection, particularly in Egypt, due to its antiviral impact and preventive effects against secondary bacterial infections. However, even at pharmacological doses, azithromycin develops rapid cardiac toxicity. Objectives: Our study here aims at investigating the cardioprotective potentials of lactoferrin, a natural compound used primarily for boosting intestinal iron absorption, to counteract azithromycin-induced cardiac toxicity in experimental rats when administered concurrently. Methods: Male Sprague Dawley rats received either lactoferrin (200 mg/kg/day, orally) or saline for 10 days. Induction of cardiac toxicity was initiated on the 6^th day via oral administration of azithromycin (20mg/kg/day, orally) for 5 successive days, concurrently with either lactoferrin or vehicle. Cardiac injuries were confirmed via Electrocardiogram (ECG) recording, assessment of cardiac function biomarkers, assessment of cardiac expression of nuclear factor erythroid 2–related factor 2 (Nrf2), interleukin-1β (IL-1β) and IL-10, measurement of cardiac oxidant/antioxidant balance, immunohistochemical staining against toll-like receptor-4 (TLR4), and nuclear factor-κB (NF-κB), and histopathological examination of HE-stained cardiac specimens. Results: Administration of azithromycin denoted a significant cardiac tissue injury as demonstrated by upregulated serum levels of cardiac biomarkers, namely total creatine Kinase (CK), Creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and Alkaline phosphatase (ALP). Furthermore, it upregulated cardiac content of malondialdehyde (MDA) and nitric oxide (NO) and cardiac inflammatory markers, such as TLR4, NF-κB, and IL-1β. Similarly, azithromycin-downregulated reduced glutathione (GSH) cardiac content and the anti-inflammatory protective indicators, IL-10 and Nrf2. Additionally, azithromycin-induced cardiotoxicity was evinced by ECG pattern and histopathologic deterioration. Oral Lactoferrin showed cardioprotective potentials and counteracted the azithromycin-induced cardiac toxicity, downregulating cardiac biomarkers. Moreover, it restored cardiac oxidant/antioxidant balance, decreased cardiac TLR4, NF-κB, and IL-1β expression, and increased IL-10 and Nrf2 expression. Lactoferrin Cardioprotective potentials were also evinced by enhanced ECG pattern and histopathological examination. Conclusion: Finally, we support the use of lactoferrin with azithromycin intake that induced cardiac toxicity.