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Background: Khamira Abresham Hakim Arshadwala (KAHAW), a distinguished, traditional Unani formulation comprising constituents of herbal, animal, and mineral origin, holds salubrious cardioprotective potential and has been used for cardiac ailments in the Unani system for ages. KAHAW is a ‘sugar-based’ preparation, which hinders its ‘claim to fame’ amongst cardiac patients with diabetes. Hence, it is fascinating to develop a novel nanoformulation of the traditional one and screen its efficacy experimentally on the male Wistar rats (4-week-old) (150-180gm). The objective was to revolutionize this historic gem of a formulation and enhance its therapeutic efficacy, a novel nanoformulation of KAHAW was developed, and its cardioprotective potential screened against isoprenaline (ISO) induced cardiotoxicity in rodents. The results were analyzed with the traditional formulations and two clinically used drugs, Ramipril and Carvedilol. Methods: Various parameters viz; Physical, Enzymatic, Non-enzymatic, and cardiac-specific biomarkers like α/β-MHC expression (Western Blot), Flow cytometry, Cardiac collagen content, and Mitochondrial enzyme assay were assessed on plasma, blood, and tissue samples followed by histomorphological investigations. Results: The effect of nanoformulation showed highly significant results (***p Conclusions: The research reiterates that the novel nanoformulation offers improved efficacy at a reduced dose against ISO-induced experimental models of myocardial necrosis.