​Doxorubicin (DOX) is a potent chemotherapeutic agent widely used to treat various cancers, but its application is restricted by dose-limiting cardiotoxicity. This study investigates the cardioprotective effects of rosmarinic acid (RosA), a natural polyphenol with antioxidant and anti-inflammatory properties, in reducing DOX-induced cardiotoxicity while maintaining its anticancer efficacy. A novel nanoparticle delivery system was developed by conjugating RosA and DOX onto polyethylene glycol (PEG)-chitosan nanoparticles (Dox-RosA-PEG-CS), characterized by a zeta potential of +14.2 mV, a hydrodynamic size of 305 ± 5 nm, and an encapsulation efficiency of 82%. Results from H9C2 cardiac myocytes exposed to DOX and RosA demonstrated that RosA mitigated cardiotoxicity by reversing DOX-induced transcriptomic alterations, including downregulating apoptosis-related, cardiac remodeling, and inflammatory signaling genes. Additionally, RosA suppressed markers of inflammation, such as C-C motif chemokine ligands 2 (CCL2) and 11 (CCL11), and inhibited troponin T expression, a key indicator of myocardial damage. Anticancer studies on MDA-MB-231 breast cancer cells confirmed that RosA did not compromise DOX's therapeutic efficacy. These findings suggest that RosA, in a nanoparticle delivery system, holds promise as a safe and effective adjunctive therapy for reducing DOX-induced cardiotoxicity, offering a novel strategy for improving the clinical utility of DOX in cancer treatment.​