Objective <p>To investigate whether herb cake-insulated moxibustion affects the expression of cholesterol metabolism-related protein 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) and inhibits the development of atherosclerosis by regulating the exosomal miR-223 expression.</p> Methods <p>Thirty-six male New Zealand rabbits were randomly assigned to a normal group, a model group, and an herb cake-insulated moxibustion group, with 12 rabbits in each group. The model and the herb cake-insulated moxibustion groups were fed a high-fat diet for 8 weeks to induce an atherosclerosis model. Following successful modeling, the herb cake-insulated moxibustion group was subjected to bundling and herb cake-insulated moxibustion intervention, while the other two groups were subjected only to bundling without moxibustion. After 8 weeks of intervention, hematoxylin-eosin (HE) staining was used to observe aortic morphology; the serum levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) were detected using an automatic biochemical analyzer in each group. Exosome morphology was observed using the transmission electron microscope; Western blotting (WB) was used to detect the protein levels of serum exosomal CD63 and CD9 markers, as well as liver HMGR; additionally, real-time fluorescence quantitative polymerase chain reaction was used to quantify serum exosomal miR-223.</p> Results <p>HE staining showed thickened aortic intima, lipid infiltration, foam cell aggregation, and structural damage to the arterial wall in the model group. Meanwhile, after modeling, the serum levels of LDL-C, TC, and TG increased significantly in the model and herb cake-insulated moxibustion groups compared to the normal group (<i>P</i>&lt;0.05), suggesting successful atherosclerosis rabbit model preparation. The serum exosomes of rabbits in the model group exhibited a saucer-like or semi-concave spherical shape with diameters of 120–150 nm. WB detection results showed positive expression of the exosomal markers CD63 and CD9. After 8 weeks of intervention, the miR-223 level in the model group was significantly lower than that in the normal group (<i>P</i>&lt;0.01). In contrast, the herb cake-insulated moxibustion group demonstrated significantly reduced serum levels of TC, TG, and LDL-C (<i>P</i>&lt;0.05), increased miR-223 expression (<i>P</i>&lt;0.01), and decreased relative liver HMGR protein expression (<i>P</i>&lt;0.05) compared to the model group.</p> Conclusion <p>Herb cake-insulated moxibustion may alleviate the progression of atherosclerosis by up-regulating exosomal miR-223 expression and down-regulating HMGR protein expression, thereby inhibiting cholesterol anabolic metabolism.</p>