To address the poor water solubility and low targeting ability of Monascus yellow pigment (MYP) from Monascus rice and thereby enhance its bioavailability, this study prepared MYP-zein-galactosylated chitosan nanoparticles (MYP-GC-NP) and evaluated its efficacy in ameliorating oleic acid/palmitic acid (OA/PA)-induced lipid accumulation in HepG2 cells. The results showed that MYP-GC-NP exhibited a spherical shape and uniform size distribution with an average particle size of (167.00 ± 0.60) nm, a polydispersity index (PDI) of 0.25 ± 0.01, and a ζ-potential of 70.88 mV. Additionally, compared with nanoparticles without modification by GC, MYP-GC-NP were more readily taken up by hepatocytes and significantly reduced intracellular lipid accumulation. This study provides a novel strategy to improve the bioavailability of MYP and offers a theoretical basis for the application of MYP-loaded nanoparticles in alleviating lipid accumulation.