Hepatocellular carcinoma (HCC) is a primary liver malignancy commonly encountered in the setting of chronic liver disease and cirrhosis. Compound Kushen Injection (CKI) has been widely used in HCC, however, the underlying mechanisms are scarce.To explore the molecular mechanisms of CKI for HCC.To explore the molecular mechanisms of CKI for HCC.The chemical ingredients of CKI were reviewed from published articles and the potential targets were got from Herbal Ingredients' Targets Platform. Coagulation-related targets were from Kyoto Encyclopedia of Genes and Genomes and HCC-related targets were from Therapeutic Target Database, Gene Expression Omnibus, and The Cancer Genome Atlas. Then the CKI-Herb-Target and CKI-Herb-Target-HCC networks were built. The shared targets between CKI and HCC were used for functional enrichment through Metascape and the shared coagulation-related target was used for molecular docking and survival analysis.A total of 23 chemical ingredients and 41 potential targets shared between CKI and HCC were obtained. The results of functional enrichment indicated that several canonical pathways of CKI mostly participated in the treatment of HCC. Furthermore, a chemical ingredient of CKI formed a stable hydrogen bond link with the ASN-189 on PLG, with a best binding energy of -4.7 kcal/mol. Finally, PLG was confirmed as the shared coagulation-related target and interrelated with the prognosis of HCC.CKI probably improves HCC prognosis through PLG. Our research undoubtedly deepened the understanding of the molecular mechanism of CKI anti-HCC.Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.