Abstract: Objective: Network pharmacology was used to predict potential compounds, targets and pathways of action in hawthorn leaves for the treatment of hyperlipidaemia, and the network pharmacology predictions were validated in conjunction with target enzyme and cellular assays. The material basis and mechanism of action of hawthorn leaves against hyperlipidemia. Methods: The chemical components of hawthorn leaves were obtained through the traditional Chinese Medicine System Pharmacology database analysis platform and literature mining, and the potential targets were obtained by using the relevant databases. GO and KEGG analysis were carried out to construct the “component-target-pathway” network. The effective components and potential targets predicted by network pharmacology were verified by ERK2 kinase, oil red O staining and triglyceride experiment. Results: After the network pharmacology screening, 96 active ingredients and 40 interacting target proteins were obtained from hawthorn leaves. The results of KEGG analysis indicated that the therapeutic effects of the active ingredient on hyperlipidaemia were mainly through the following signalling pathways: Metabolic pathway, AMPK signaling pathway, HIF-1 signaling pathway, insulin resistance, thyroid hormone signaling pathway. According to the prediction results of network pharmacology, combined with the representative compounds of hawthorn leaves isolated by the research group, the ERK2 kinase activity of six compounds such as vitexin was tested. The results showed that the inhibition rate of vitexin on ERK2 kinase was the highest, reaching 84%. By constructing high-fat HepG2 cell model, oil red O staining and quantitative experiment were carried out, and TG content was measured. It was found that after vitexin intervention, the number of lipid droplets in cells gradually decreased with the increasing of vitexin concentration, and TG content decreased, indicating that vitexin could reduce lipid accumulation and TG content in cells. Further, the results of network pharmacology predicted the anti hyperlipidemia effect of vitexin in hawthorn leaves were verified. Conclusion: In this paper, network pharmacology was used to predict the material basis and mechanism of action of compounds in hawthorn leaves against hyperlipidemia. Target enzyme, oil red O staining and TG quantification experiments initially confirmed the network pharmacology predictions, while suggesting that vitexin would be promising as a potential therapeutic compound for reducing intracellular lipid content.