Hypercholesterolemia in recent years has become a serious problem because of its cause of almost half of cases of ischemic heart disease. Alternative medicine most people usually use also has a weakness, namely weak pharmacological effects. This study aims to optimize the pharmacological effect of kirinyuh leaves as an antihypercholesterolemic agent by making nanoparticles preparations. This study used in silico and in vivo studies, the in silico study was done to predict the potential of flavonoid, one of kirinyuh leaves’ compounds which can inhibit HMG-CoA reductase (HMGCR) enzyme, that have a role of cholesterol making. In vivo study was done to hypercholesterolemia mouse model (n=24) who were given of kirinyuh leaves extract each with 100 mg (T1) and 200 mg/200 g body weight (BW) (T2) dose, and kirinyuh leaves extract in nanoparticle formulas each 1 mL (T3) and 2 mL/200 g BW (T4) every day for 2 weeks. Blood was snipped at the end of treatment for lipid profile analysis. Molecular docking’s result showed that flavonoid compounds can reduce hypercholesterolemia by interacting with HMGCR enzymes thus the formation of cholesterol in the liver can be inhibited, therefore T1-T4 are capable to improve blood lipid profile significantly compared to control (P<0.05). The best result is shown in T4 that gave 2 mL/200 g BW dose of nanoparticle formulation with the most reduction of total cholesterol and lipid profile between all the treatment groups. It can be concluded that nanoparticle formulation has better pharmacologist effect.