Luteolin is a kind of natural flavonoid with great potential for lipid accumulation intervention. However, the poor water solubility and non-targeted release greatly diminish its efficiency. In this study, 4-aminophenyl β-D-galactopyranoside (Gal-NH)/mulberry leaf polysaccharides- lysozyme/luteolin nanoparticles (Gal-MPL/Lut) were fabricated via amide reaction, self-assembly process and electrostatic interaction. The nanoparticles could hepatic-target of Lut and enhance action on liver tissue by specific recognition of asialoglycoprotein receptor (ASGPR). Physicochemical characterization of the nanoparticles showed a spherical shape with a uniform particle size distribution (77.8 ± 2.6 nm) with a polydispersity index (PDI) of 0.22 ± 0.06. Subsequently, in HepG2 cells model, administration with hepatic-targeted Gal-MPL/Lut nanoparticles promoted the cellular uptake of Lut, and regulated lipid metabolism manifested by remarkably inhibiting total cholesterol (TC) and triglyceride (TG) expression levels through the modulation of PI3K/SIRT-1/FAS/CEBP-α signaling pathway. This study provides a promising strategy for a highly hepatic-targeted therapy to ameliorate lipid accumulation using natural medicines facilitated by nano-technology.