Atherosclerosis (AS), characterized by a chronic inflammatory disease, is a top cause of morbidity and disability worldwide. During the pathogenesis of AS, the leading process of inflammation highly involves a secondary event of oxidative stress, but limited antioxidants are currently available clinically due to their nonspecific effects, poor biosafety, and rapid in vivo elimination and urinary excretion as well as short retention time within plaque lesions. In this work, Prussian blue nanozymes with a strong reactive oxygen species (ROS)-scavenging ability were rationally engineered for efficient AS nanotherapy. Specifically, the obtained nanozymes with high photothermal performance could behave as potent photoacoustic imaging agents for plaque detection. In addition, these nanozymes featuring multienzyme activities could reduce the cellular ROS level, exert cytoprotective effects against ROS-mediated macrophages apoptosis, and inhibit foam cell formation, significantly boycotting AS development. The underlying mechanism was further verified by transcriptome sequencing at the cellular level and a series of immunohistochemical staining of aortic sinus sections in apoE-/- mice. Finally, the high biocompatibility and biosafety of the engineered Prussian blue nanozymes further guarantee their clinical translation potential for AS management.