The present study evaluated the ameliorative effects of Naringenin (NG) against 5-Flourouracil (5-FU) induced cardiotoxicity in Wistar rats. A total of 48 male rats of uniform size were divided into 4 groups of 12 animals each. Control group 1 received normal saline (NS) per oral (P/O), group 2 served as 5-FU toxic was injected intraperitoneal (IP) (@ 20 mg/kg b.wt.) for first 5 days, group 3 received NG orally (100 mg/kg b. wt/day) for 28 days and group 4 was injected IP with 5-FU + NG P/O for 28 days and sacrificed on 14th and 28th day of experiment. NG treatment significantly reduces increased left ventricular wall thickness, cardiac markers-lactate dehydrogenase (LDH), creatine kinase myocardial band (CK-MB), cardiac troponin-I (cTn-I) and C-reactive protein (CRP)in serum in group 2 on 14th day and 28th day of the experiment. On microscopic examination, severe congestion of blood vessels along with degeneration of cardiac myocytes were noticed. At the same time, mild tissue alteration was observed in NG treatment group. On ultrastructurally, in SEM, a mild decrease in degenerative changes in tissue structure was observed in group4 rats. In conclusion, the findings underscore the substantial potential of NG in mitigating 5-FU-induced cardiotoxicity.