Abstract: Objective: Chitosan-coated nuciferine liposomes (CS-LP) were prepared and their hypolipidemic effects in vivo were investigated. Methods: The CS-LP were prepared by thin film dispersion and pH gradient methods, and their particle size and potential distribution, encapsulation rate, microscopic morphology and in vitro release curves were determined, and their hypolipidemic effects on obese mice were investigated. Results: The CS-LP was produced in a homogeneous spherical structure with a particle size of 253.54±4.25 nm, a zeta potential of 32.50±3.44 mV. The encapsulation rate of CS-LP was 83.46%. Compared with nuciferine liposomes (LP), the stability of CS-LP in the simulated digestive solution was improved after adding the chitosan. Compared with the high-fat group, mice gavaged with CS-LP for 11 weeks showed a 12.91% and 41.03% significant reduction in body weight and adipose tissue weight, respectively (P<0.05), a 32.40% and 14.49% significant reduction in serum triglyceride and LDL cholesterol mass concentrations, respectively (P<0.05), and a normalization of lipid levels and a reduction in adipocyte volume. High-throughput sequencing analysis showed that CS-LP significantly increased the diversity of intestinal flora in mice (P<0.05). At the phylum level, the relative abundance of the thick-walled phylum and the relative abundance of the bacillus phylum increased significantly, and the ratio of the campylobacter and thick-walled phylum to the relative abundance of the mimic phylum also significantly decreased (P<0.05). Conclusion: The chitosan-coated nuciferine liposomes with high encapsulation rate and slow release could effectively improve obesity and intestinal flora disorders in mice caused by high-fat diet, and express the broad application prospects in the development of lipid-lowering formulations.