Lobelia chinensis Lour. (LCL) is a common herb used for clearing heat and detoxifying, and it has antitumor activity. Quercetin is one of its important components, which may play an important role in the treatment of hepatocellular carcinoma (HCC).To study the active ingredients of LCL, their mechanism of action on HCC, and lay the foundations for the development of new drugs for the treatment of HCC.Network pharmacology was used to examine the probable active ingredients and mechanisms of action of LCL in HCC treatment. Based on an oral bioavailability of ≥30% and a drug-likeness index of ≥0.18, relevant compounds were selected from the Traditional Chinese Medicine Systems Pharmacology database and TCM Database@Taiwan. HCC-related targets were identified using gene cards and the Online Mendelian Inheritance in Man (OMIM) database. A Venn diagram was created to assess the relationship between the intersection of disease and medication targets by creating a protein-protein interaction network, and the hub targets were selected by topology. Gene Ontology enrichment analyses were performed using the DAVID tool. Finally, in vivo and in vitro experiments (qRT-PCR, western blotting, hematoxylin and eosin staining, transwell assays, scratch tests, and flow cytometry assays) verified that LCL demonstrated notable therapeutic effects on HCC.In total, 16 bioactive LCL compounds met the screening criteria. The 30 most important LCL therapeutic target genes were identified. Of these, AKT1 and MAPK1 were the most important target genes, and the AKT signaling pathway was identified as the key pathway. Transwell and scratch assays showed that LCL prevented cell migration, and flow cytometry tests revealed that the LCL-treated group showed a considerably higher rate of apoptosis than the control group. LCL reduced tumor formation in mice in vivo, and Western blot analysis of tumor tissues treated with LCL indicated variations in PTEN, p-MAPK and p-AKT1 levels. The results show that LCL may inhibit the progression of HCC through the PTEN/AKT signaling pathway to achieve the goal of treating HCC.LCL is a broad-spectrum anticancer agent. These findings reveal potential treatment targets and strategies for preventing the spread of cancer, which could aid in screening potential traditional Chinese medicine for anticancer and clarifying their mechanisms.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.