Treatment with Lipitor is associated with several adverse impacts. Here we investigated the effects of low Lipitor nanoparticles (atorvastatin calcium nanopartilcle [AC-NP]), with size less than 100 , on enzymes of lipid metabolism and inflammation in cardiac, hepatic, and brain tissues of hypercholestremic adult male rats. Adult male rats were divided into five experimental groups. In group 1, the intact control (normal pellet diet), animals were fed a normal control diet; the other four groups were fed a high-fat diet (HFD) for 6 weeks. After 6 weeks, groups from 2 to 5 were assigned as a positive control (HFD), HFD + Lipitor, HFD + AC-NP-R1, or HFD + AC-NP-R2. Different treatments were administrated orally for two regimen periods (R1 daily and R2 once every 3 days). The treatment was conducted for two consecutive weeks. The HFD group faced a significant elevation in 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), associated with a significant reduction in low-density lipoprotein receptor (LDL-R) along with cholesterol 7 α-hydroxylase enzyme in hepatic tissues, compared with the control group. Also, the HFD group induced hepatic, cardiac, and brain inflammation, evidenced by increased hepatic oxidative stress markers and cardiac homocysteine, together with elevated proinflammatory cytokines interleukin-1β (IL-1β) and IL-6 levels in brain tissue, compared with the control group. Different AC-NP treatments significantly augmented both mRNA LDL-R and mRNA 7α-hydroxylase expression in hepatic tissues, associated with significant depletion in mRNA HMG-CoA expression, compared with HFD + Lipitor. The inflammation symptoms were ameliorated by the AC-NP treatments, compared to HFD + Lipitor. Lipitor encapsulation in NP formulation results in increased efficiency and reduced dose-related adverse effects known to be associated with the Lipitor chronic administration.