Doxorubicin is a highly effective, first line chemotherapeutic agent used in the management of hematological and solid tumors. The effective use of doxorubicin in cancer therapy has been severely limited owing to its well-documented cardiotoxic side effect. Oxidative stress, lipid peroxidation, apoptosis as well as dysregulation of autophagy, has been implicated as a major contributor associated with doxorubicin-induced cardiotoxicity. Increased oxidative stress and lipid peroxidation are known to enhance the production of reactive oxygen species, while autophagy has been reported to protect the cell from stress stimuli or, alternatively, contribute to cell death. Nonetheless, to date, no single chemical synthesized drug is available to prevent the harmful action of doxorubicin without reducing its anti-cancer efficacy. Therefore, the search for an effective and safe antagonist of doxorubicin-induced cardiotoxicity remains a challenge. In recent years, there has been much interest in the role plant-derived polyphenols play in the regulation of oxidative stress and autophagy. Therefore, the present review renders a concise overview of the mechanism associated with doxorubicin-induced cardiotoxicity as well as giving insight into the role plant-derived phytochemical play as a possible adjunctive therapy against the development of doxorubicin-induced cardiotoxicity.