Anthracyclines, such as doxorubicin and epirubicin (EPI), are integral in the treatment of solid tumors and hematological malignancies but are associated with cardiotoxicity, potentially leading to heart failure. The underlying mechanisms involve the generation of reactive oxygen species (ROS), alterations in iron metabolism, and the inhibition of topoisomerase 2β (Top2β), resulting in mitochondrial dysfunction and cell death. Fluoroquinolones, including ciprofloxacin (CPX), enhance the efficacy of anthracyclines by inhibiting topoisomerase II and inducing apoptosis, thereby indicating a promising combination therapy. This study investigated the impact of environmental pH on the cardiotoxicity and myocardial accumulation of anthracyclines, as well as the cardioprotective and synergistic potential of CPX when co-administered with epirubicin. The findings revealed that only the zwitterionic form of CPX, either free or encapsulated in liposomes, offers significant cardioprotection without compromising the anticancer activity of EPI. Remarkably, the combination of liposomal CPX and EPI completely attenuates EPI's cardiotoxicity. These results suggest that initiating treatment with liposomal CPX prior to EPI administration may optimize cardioprotection while maintaining therapeutic efficacy against cancer.