Doxorubicin (DOX) is used for the treatment of various malignancies, including leukemias, lymphomas, sarcomas, and bladder, breast, and gynecological cancers in adults, adolescents, and children. However, DOX causes severe side effects in patients, such as cardiotoxicity, which encompasses heart failure, arrhythmia, and myocardial infarction. DOX-induced cardiotoxicity (DIC) is based on the combination of nuclear-mediated cardiomyocyte death and mitochondrial-mediated death. Oxidative stress, altered autophagy, inflammation, and apoptosis/ferroptosis represent the main pathogenetic mechanisms responsible for DIC. In addition, in vitro and in vivo models of DIC sirtuins (SIRT), and especially, SIRT 1 are reduced, and this event contributes to cardiac damage. In fact, SIRT 1 inhibits reactive oxygen species and NF-kB activation, thus improving myocardial oxidative stress and cardiac remodeling. Therefore, the recovery of SIRT 1 during DIC may represent a therapeutic strategy to limit DIC progression. Natural products, i.e., polyphenols, as well as nano formulations of DOX and iron chelators, are other potential compounds experimented with in models of DIC. At present, few clinical trials are available to confirm the efficacy of these products in DIC. The aim of this review is the description of the pathophysiology of DIC as well as potential drug targets to alleviate DIC.