Cardiotoxicity is doxorubicin's primary side effect. Its cardiac toxicity has been attributed to the generation of free radicals. The present work was designed to understand the potential underlying pathways behind the cardioprotective action of diosmin (Dio) and Dio-loaded chitosan nanoparticles (DCNPs) against doxorubicin (Dox)-mediated cardiotoxicity. Male rats were allocated into five groups: control, Dio (100 mg/kg), Dox (12 mg/kg), Dio + Dox (100 mg/kg + 12 mg/kg), and DCNPs+Dox (100 mg/kg DCNPs/orally+12 mg/kg Dox/IP). Notably, in response to Dox, a significant increase of cardiac biomarkers with a decrease in Na