Chemotherapeutic drugs are a known factor that impairs the system of life due to their severe side effects. A more worrying fact is that the patients administered with doxorubicin fall under the risk of cardiotoxicity. The evolution of exploring plant-derived compounds is a possible way to combat health issues in therapeutic applications. Hence, this study focuses on the protective effect of plant-based compound nuciferine (NFN) against doxorubicin-induced cardiotoxicity in both in vitro and in vivo models. In this investigation, nuciferine significantly reduces DOX-mediated cardiotoxicity by mitigating reactive oxygen species, thereby preventing DNA fragmentation, regulating apoptosis genes and reducing the caspase 3/7 levels in vitro. Besides, nuciferine has shown significant protection against DOX-induced cardiac impairment and the upregulation of cardiogenic markers in vivo. The DOX-induced oxidative stress can be mitigated via enhancing the endogenous antioxidants, thereby controlling ROS-mediated apoptosis. In virtue of these potential features, nuciferine can be a budding candidate to address therapeutic needs. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.