Abstract：Objective：To explore Huqi San's mechanism of action in treating primary liver cancer based on network pharmacology and molecular docking technology. Methods：The active ingredients of Huqi San were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP)； primary liver cancer-related genes were screened using GeneCards， OMIM， and PharmGkb databases， and medicinals-disease cross targets were obtained using R software. Cytoscape 3.7.2 software was used to construct a network diagram of active ingredients-targets-primary liver cancer in Huqi San for medicinals-disease cross targets and active ingredients and screen out core components. The STRING platform was used for protein-protein interaction (PPI) network analysis of medicinals-disease cross targets； clustering analysis was performed with the MCODE plugin to obtain key targets related to the prognosis of primary liver cancer patients；the primary liver cancer cohorts in the TCGA database were used for the prognosis analysis of key targets. Gene Ontology (GO) -based functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on the target genes using R language software package， and molecular docking validation was performed on the main active ingredients and key targets using AutoDock Vina software. Results：A total of 113 active ingredients， 226 acting targets， and 1 765 disease targets were screened from Huqi San， and 116 core anti-primary liver cancer targets were predicted. The key components of Huqi San in the treatment of primary liver cancer included quercetin，kaempferol，luteolin，naringenin，tanshinoneⅡA，etc. The PPI network showed that estrogen receptor 1 (ESR1)， caspase 3 (CASP3)， the tumor suppressor protein 53 (TP53)， B-cell lymphoma 2 (BCL2)，signal transducer and activator of transcription 3 (STAT3)，mitogen-activated protein kinase 3 (MAPK3)， cyclin D1 (CCND1)， mitogen-activated protein kinase 1 (MAPK1)， Fos oncogene (FOS)， protein kinase B1 (AKT1)， and heat shock protein 90 α family A member 1 (HSP90AA1) were key targets for the treatment of primary liver cancer with Huqi San. Prognosis analysis showed that the expression of ESR1，CASP3，MAPK3，AKT1，and HSP90AA1 was closely related to the survival time of primary liver cancer patients. Enrichment analysis revealed that Huqi San mainly played a role in cellular processes such as cellular responses to chemical stress， reactions to reactive oxides， responses to lipopolysaccharides， and responses to foreign body stimulation， and it could regulate multiple signaling pathways， including phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling pathway， interleukin-17 (IL-17) signaling pathway， and tumor necrosis factor (TNF) signaling pathway， to exert therapeutic effects. Molecular docking showed that key targets TP53，AKT1，STAT3，ESR1，and MAPK1 could stably bind to naringenin， kaempferol， quercetin， and luteolin. Conclusion： The components of Huqi San，such as naringenin，kaempferol，quercetin，and luteolin，can act on multiple targets such as AKT1，ESR1，CASP3，and MAPK3，and exert therapeutic effects on primary liver cancer by regulating the PI3K-AKT signaling pathway and the IL-17 signaling pathway.