The present study reports protective effect of hydro-alcoholic extract of Luffa acutangula (HAELA) on doxorubicin (DXR) induced cardio and nephrotoxicity in mice by studying various serum biomarkers, antioxidants in target organs and histoarchitecture alterations. Pretreatment with HAELA reversed significantly the elevated serum biomarkers, alanine amino transferase, lactate dehydrogenase and creatinine phosphokinase in heart and kidney in DXR treated mice. In addition, HAELA treatment inhibited elevated malondialdehyde formation and restored the depleted glutathione, catalase, superoxide dismutase in heart and kidney tissue. The altered histoarchitecture of heart and kidney tissue due to DXR treatment were also improved with HAELA. The protective activity observed with HAELA on DXR induced cardio and nephrotoxicity in mice was found to be related to its antioxidant property which finally results in membrane stabilization.