Objective To construct a simvastatin nano drug delivery system and explore its effect on atherosclerosis model rats. Methods Laser confocal microscopy was used to detect the cell uptake capacity of simvastatin nanoparticles. Rats were randomly divided into a model group (Model), simvastatin group (Sim), simvastatin nanoparticle group (Sim-LPNs), and control group (Control, normal rats), with 10 animals per group. A biochemical analyzer was used to detect TG, TC, LDL-C, and HDL-C levels. HE staining was used to detect pathological changes in arteries and vessels. Western blot was used to detect changes in p-AMPK and p-ACC protein levels. Results Sim-LPNs had a uniform spherical appearance with a mean dynamic diameter of 180 ± 23 nm. Compared with COU-6 treatment, the green fluorescence intensity of Caco-2 cells treated with COU-6-LPNs was significantly enhanced (P<0. 01). Compared with the Control group, the TC, TG and LDL-C levels in the Model group were significantly increased, and HDL-C was significantly decreased (P<0. 01). Compared with the Model group, the Sim group had significantly lower TC and LDL-C levels (P< 0. 01 or P<0. 05). Compared with the Model group, the Sim-LPNs group had significantly reduced TC, TG, and LDL-C levels, as well as significantly increased HDL-C levels (P<0. 01). Compared with the Sim group, TC and LDL-C levels in Sim-LPNs rats were significantly reduced ( P< 0. 01). In the Model group, mucosal degeneration, edema, and typical atherosclerotic plaques with a thick lipid core and foam cells were observed in the arterial blood vessel walls. The Sim group showed some improvement, but the Sim-LPNs group had a more obvious improvement. Compared with the Control group, the relative plaque area and relative plaque area / total surface of the arterial blood vessel wall of the Model group were significantly increased (P<0. 01). Compared with the Model group, the relative plaque area and the relative plaque area / total surface of the arterial wall of the Sim-LPNs groups were significantly reduced (P<0. 01). Compared with the Control group, the expressions of p-AMPK and p-ACC proteins in the liver tissues of the Model group were significantly downregulated ( P < 0. 01). Compared with the model group, the expression of p-AMPK protein in the Sim group was significantly increased (P< 0. 05), and the expressions of p-AMPK and p-ACC proteins in the Sim-LPNs groups were significantly increased (P<0. 05 or P<0. 01). Compared with the Sim group, p-AMPK protein expression in the Sim-LPNs groups was significantly upregulated (P<0. 01). Conclusions Simvastatin nanoparticles have a good anti-atherosclerotic effect, which may be related to the enhanced absorption of small intestinal cells and activation of the liver cell AMPK-ACC signaling pathway to regulate blood lipid levels.