AbstractExposure to micro‐ and nanoplastics (MNPs) is common because of their omnipresence in environment. Recent studies have revealed that MNPs may cause atherosclerosis, but the underlying mechanism remains unclear. To address this bottleneck,ApoE−/−mice are exposed to 2.5–250 mg kg−1polystyrene nanoplastics (PS‐NPs, 50 nm) by oral gavage with a high‐fat diet for 19 weeks. It is found that PS‐NPs in blood and aorta of mouse exacerbate the artery stiffness and promote atherosclerotic plaque formation. PS‐NPs activate phagocytosis of M1‐macrophage in the aorta, manifesting as upregulation of macrophage receptor with collagenous structure (MARCO). Moreover, PS‐NPs disrupt lipid metabolism and increase long‐chain acyl carnitines (LCACs). LCAC accumulation is attributed to the PS‐NP‐inhibited hepatic carnitine palmitoyltransferase 2. PS‐NPs, as well as LCACs alone, aggravate lipid accumulation via upregulating MARCO in the oxidized low‐density lipoprotein‐activated foam cells. Finally, synergistic effects of PS‐NPs and LCACs on increasing total cholesterol in foam cells are found. Overall, this study indicates that LCACs aggravate PS‐NP‐induced atherosclerosis by upregulating MARCO. This study offers new insight into the mechanisms underlying MNP‐induced cardiovascular toxicity, and highlights the combined effects of MNPs with endogenous metabolites on the cardiovascular system, which warrant further study.