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Background: Atherosclerosis is a systemic disease affecting the entire arterial tree involving the accumulation of inflammatory cells in the atherosclerotic plaques with larger macrophage-rich areas. Utilizing this property, we aimed to study the effect of atorvastatin nanoparticles given once in a week compared to free atorvastatin given daily on the plaque properties in a rabbit model of atherosclerosis. Materials and Methods: Rabbits were fed with high-cholesterol diet over a period of 2 months. Thereafter, aortic wall tissues were taken for histological changes, and morphometric analysis and plasma samples were taken for the measurement of lipid profile. Results: Our nanoformulation has been effective in improving lipid profile and decreasing plaque content in the aortic wall and showed comparable effect with that of a free drug. Conclusion: Thus, our novelty is the development of sustained-release nanoformulation of atorvastatin having similar pharmacodynamic activity when compared to free atorvastatin.