Cancer is a growing public health problem; it is responsible annually for millions of deaths worldwide. Fluoropyrimidines are highly effective and commonly prescribed anti-neoplastic drugs used in a wide range of chemotherapy regimens against several types of malignancies. 5-fluorouracil and its prodrugs affect neoplastic cells in multiple ways by impairing their proliferation, principally through the inhibition of thymidylate synthase. Fluoropyrimidine-induced cardiotoxicity was described more than 50 years ago, but many details such as incidence, mechanisms, and treatment are unclear and remain disputed. Severe cardiotoxicity is not only life-threatening, but also leads to withdrawal from an optimal chemotherapy regimen and decreases survival rate. Differences in the frequency of cardiotoxicity are explained by different chemotherapy schedules, doses, criteria, and populations. Proposed pathophysiological mechanisms include coronary vasospasm, endothelial damage, oxidative stress, Krebs cycle disturbances, and toxic metabolites. Such varied pathophysiology of the cardiotoxicity phenomenon makes prevention and treatment more difficult. Cardiovascular disturbances, including chest pain, arrhythmias, and myocardial infarction, are among the most common side effects of this class of anti-neoplastic medication. This study aims to summarize the available data on fluoropyrimidine cardiotoxicity with respect to symptoms, incidence, metabolism, pathophysiological mechanism, diagnosis, management, and resistance.