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Doxorubicin (DOX) is a commonly used anthracycline in treatments of leukemia, lymphoma and breast cancer in humans and has been limited by its cardiotoxicity, which is manifested congestive heart failure in the worst condition. The present study showed that the marine carotenoid of fucoxanthin could exert cardioprotective effect against the DOX-induced injury in ICR mice. And then, the protective effects and mechanisms of fucoxanthin on DOX-induced injury of neonatal rat cardiomyocytes were investigated. The results demonstrated that fucoxanthin significantly reduced mice toxic death triggered by DOX. The protective effects were also showed by the suppression of apoptotic cell death in cardiomyocytes. Further study revealed that fucoxanthin-produced suppression of MAPK activated by DOX was involved in the cardioprotection. The findings confirmed the cardioprotective effect of fucoxanthin against DOX-induced cardiotoxicity by protecting myocardial cells from lipid peroxidation and apoptosis, which would likely result in an increased therapeutic window of DOX in cancer therapy.