Abstract: Objective: To investigate the effect and potential mechanism of lychee kernel extract in the intervention of non-alcoholic fatty liver disease (Nonalcoholic fatty liver disease, NAFLD) based on network pharmacology. Methods: The components and action targets of litchi nuclei were obtained from the Pharmacology Database and Analysis Platform (TCMSP) within the Chinese Medicine System, the disease targets of NAFLD were obtained using disease target data from GeneCard, the intersection and pathway-target interaction network diagram were obtained through Cytoscape, and the GO bioprocess analysis and KEGG pathway enrichment analysis were performed using Bioinformatics website. This study established an animal model with diet-induced obsisity mouse NAFLD and administered LKE via the gastric route. HE staining indicated lipid changes in the liver. The biological kits detect content of TG, TC, ALT, and AST. Results: Eighteen potential active ingredients of litchi nuclei were identified, and 52 targets intersected with NAFLD disease. The key targets were INS, TNF, and HSP90AA1. KEGG channel enrichment filtered 20 signal pathways, the main ones include: Pathways in cancer, fluid shear stress and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications. The liver lesions of the mice in the model group were severe, the liver lesions of the mice in the drug group were significantly reduced compared with the model group, and the serum transaminases of the mice in the drug group were also significantly reduced, which was close to the normal group, and the blood lipid metabolism of the drug group also tended to be normal group,and the differences were significant (P<0.05). Conclusion: Litchi nuclei might play a role in the treatment of NAFLD by acting on such targets as INS, TNF and HSP90AA1, and modulate lipid and atherosclerotic pathways.