Atherosclerosis, characterized by dyslipidemia and severe inflammation, has become the main cause of cardiovascular disease. However, accurately and efficiently regulating lipid metabolism and relieving inflammation is a great challenge. Herein, we design a plaque/macrophage dual-targeting programmed atherosclerosis management strategy for synchronously regulating lipid metabolism and the macrophage phenotype. First, the biomimetic nanoparticles (named HA-ML@(H + R) NPs) were constructed by coloading rosuvastatin and hydroxysafflor yellow A into the hyaluronic acid (HA)-modified hybrid macrophage membrane-liposome NPs, enabling them to target plaques and macrophages simultaneously. The in vitro assay indicated that HA-ML@(H + R) NPs exhibited distinguishing antioxidant ability and reversed the macrophage phenotype from M1 to M2. Meanwhile, autophagy activation via downregulating the CD36 level promoted lipid metabolism for eliminating low-density lipoproteins. The in vivo study showed that HA-ML@(H + R) NPs exhibited therapeutic advantages in homocysteine (Hcy)-induced ApoE mice with atherosclerosis by effectively reducing the atherosclerotic plaque area and enhancing plaque stability, which was accompanied by the improvement of mice behaviors. Overall, this precise regulation of lipid metabolism and inflammation using a dual-targeted strategy provides a potentially effective method for the clinical treatment of atherosclerosis.