This study examines the protective effects of omega-3 fatty acids (OMG), a frequently used nutritional therapy in cancer patients, against doxorubicin (DOX)-induced acute cardiorenal toxicity in rats, and evaluates the cytotoxic activity of DOX when used with OMG against breast cancer cell line. Five groups of rats were treated for 4 consecutive weeks with vehicle (groups I & II), or OMG (25, 50 or 100 mg/kg/day, po; groups III, IV & V, respectively). After twenty-four hours, the last four groups were injected with DOX (200 mg/kg, ip). In DOX-treated rats, the altered ECG, serum cardiac and renal function biomarkers, and histopathological features indicated the induction of cardiorenal toxicity. Increased oxidative and apoptotic markers in both organs was observed, with elevated renal contents of NADPH-oxidase-4 (Nox4) and renin. OMG pretreatment improved those DOX-induced impairments in a dose-dependent manner, and showed antioxidant and antiapoptotic effects with regulation of renal Nox4 expression. The in-vitro study showed preservation of the cytotoxic activity of DOX on MCF7 cell line in the presence of OMG. The data suggests OMG for protection against acute DOX-induced cardiorenal damage without affecting the latter antitumor activity. It proposes regulation of oxidative stress, Nox4 activity and apoptosis as contributing protective mechanisms.