Simvastatin is a potent statin with antioxidant and anti-inflammatory characteristics, often used to treat hyperlipidemia and related cardiovascular disorders. Nonetheless, its therapeutic advantages are limited by poor water solubility and substantial degradation by CYP3A4 enzymes. This research aimed to improve simvastatin’s physicochemical characteristics and therapeutic effectiveness by developing 3D-dendritic mesoporous silica nanoparticles as nanocarriers. Dendritic silica nanoparticles were manufactured using a one-pot biphase stratification process and then surface-modified with aminopropyl groups to enhance drug loading and release characteristics. The optimization of loading parameters, such as solvent type, drug-to-carrier ratio, and loading duration, produced dendritic spherical nanoparticles with a uniform size (< 200 nm), a zeta potential of + 21 mV, and a substantial drug loading capacity (> 20%). Characterization verified the conversion of crystalline simvastatin into an amorphous state, promoting improved saturation solubility and demonstrating sustained release via a Fickian diffusion mechanism. In vivo assessments revealed enhanced antihyperlipidemic, antioxidant properties, and considerable protection against oxidative damage in a poloxamer-407-induced hyperlipidemia model. Histological evaluations of liver and aorta tissues demonstrated almost normal morphology, highlighting the safety and usefulness of the nanoparticles. These results emphasized the potential of aminated dendritic silica nanoparticles as an effective platform for enhancing simvastatin therapeutic efficacy.