Doxorubicin (DOX) is a potent chemotherapeutic agent. Unfortunately, due to the incidence of dose-dependent cardiotoxicity, its clinical usage is hampered. Natural products are gaining popularity as a means of preventing DOX-induced cardiotoxicity. In the present study, we investigated the cardiotoxic effects of DOX and assessed the potential ameliorative effects of Achillea fragrantissima extract, its combined ethyl acetate/ n. butanol (EtOAc-Bu) fraction, and vitamin E in adult male albino rats. Rats were randomly divided into five groups: Control, DOX, DOX + A. fragrantissima crude extract, DOX + its (EtOAc-Bu) fraction, DOX + Vitamin E. A single dose of DOX (15 mg/kg) was given intraperitoneally (ip) in each group except the control. Rats were assessed before scarification for arterial blood pressure and ECG recordings. Serum and heart tissue were collected for biochemical, and histopathological assessment. Pre-treatment with vitamin E, A. fragrantissima crude extract, and its (EtOAc-Bu) fraction ameliorated DOX-induced cardiotoxicity, in varying degrees and with varying significance, as evidenced by reversing the DOX-induced ECG changes, reducing serum cardiac enzymes, and improving DOX-induced histopathological changes. All the suggested protective measures, in varying degrees and with varying significance, reduced the oxidative stress, lipid peroxidation, and apoptosis markers (reduced NO, and MDA, down-regulated mRNA expression of both iNOS and caspase-3), and elevated the antioxidants markers (GR, SOD, and TAC). We concluded that such suggested natural products might offer a promising chemo-preventive approach against cardiotoxicity induced by DOX.