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Cardiotoxicity is the serious side effect of doxorubicin treatment. Ceramides are formed from the degradation of sphingolipids in cell membranes and play an important role in signaling and modulating biological processes. There is evidence that omega-3 fatty acid administration can act on this pathway. To evaluate the role of the ceramide pathway in the pathophysiology of doxorubicin-induced cardiotoxicity and the effect of omega-3 fatty acid supplementation in the attenuation of chronic doxorubicin-induced cardiotoxicity in rats. Sixty male Wistar rats were divided into four groups: Control (C), Doxorubicin (D), Omega-3 fatty acids (W), and Doxorubicin + Omega-3 fatty acids (DW). The groups received omega-3 fatty acids (400 mg/kg/day, via gavage) or water for 6 weeks and doxorubicin (3.5 mg/kg, intraperitoneal) or saline once a week for 4 weeks. Doxorubicin-treated animals showed increases in left atrium and left ventricle diameters, serum triglycerides and cholesterol, malondialdehyde, and protein carbonylation. We also observed a decrease in left ventricular shortening fraction and nSMase1 expression in the heart. Omega-3 fatty acid supplementation attenuated the structural and functional alterations caused by doxorubicin and decreased protein carbonylation. In contrast to doxorubicin, omega-3 fatty acids increased neutral nSMase activity in animals that both received and did not receive doxorubicin but with no effect on nSMase1 protein expression. Omega-3 fatty acid supplementation attenuated the cardiotoxicity caused by doxorubicin. The ceramide pathway may be involved in the pathophysiology of cardiotoxicity, but it is not the mechanism by which omega-3 fatty acids attenuated cardiac dysfunction., Competing Interests: The authors declare that they do not have any conflict of interest., (© 2024 The Author(s). Food Science & Nutrition published by Wiley Periodicals LLC.)