Doxorubicin (DOX), a widely used anthracycline chemotherapeutic, is clinically limited by cumulative and dose-dependent cardiotoxicity. Oxidative stress and inflammation are central pathogenic mechanisms of DOX-induced cardiomyopathy (DIC), characterized by extensive innate immune cells infiltration into the injured myocardium. The immune landscape of DIC mouse models is systematically characterized, identifying macrophages as the predominant immune subset. Based on this, a hybrid nanozyme (PB@CeO2 NPs) is developed, comprising Prussian blue nanoparticles (PB NPs) and cerium oxide nanoparticles (CeO2 NPs). The PB NPs core provides magnetic resonance imaging (MRI) contrast, while CeO2 NPs surface modification enhances immune cell uptake, promotes retention in inflamed cardiac tissue, and augments reactive oxygen species (ROS) scavenging and anti-inflammatory efficacy. In vitro experiments demonstrate that PB@CeO2 NPs alleviate mitochondrial damage, inhibit apoptosis, and induce macrophage M2 polarization. In vivo studies show that PB@CeO2 NPs facilitate myocardial accumulation, reduce cardiac inflammation and fibrosis, and improve cardiac function. By integrating the antioxidative and anti-inflammatory effects of PB@CeO2 NPs with inflammation-mediated immune cell retention in injured myocardium, this study presents a promising nanotherapeutic platform for targeted and precise intervention in anthracycline-induced cardiotoxicity.© 2025 Wiley‐VCH GmbH.