<p>The anti-hepatocellular carcinoma (HCC) effect of the active ingredients of natural Chinese herbal medicine has become a hot topic at home and abroad. A list of studies evidence the therapeutic efficacy of Dahuang (DH) or Dangshen (DS) against HCC, but the combination effect of DH and DS in HCC treatment is rarely reported and the molecular mechanism of the drug pairs is not yet clear. Therefore, in this study, the combined effects and potential mechanisms of DH and DS drug pairs were investigated through network pharmacology, bioinformatics, molecular docking, and a series of pharmacological experiments, including the MTT assay, clone formation, wound healing, JC-1 staining, and western blotting. In total, 140 intersection targets between the DH–DS drug pairs and HCC were identified. In the PPI network, the top ten hub targets with the highest node connection values were VEGFA, AKT, CTNNB1, EGFR, TNF, CASP3, HRAS, SRC, JUN, and ESR1. GO functional and KEGG pathway enrichment analysis involved 289 biological processes, 33 cellular components, 57 molecular functions, and 143 signaling pathways. Bioinformatic analysis indicated that EGFR and AKT were promising candidate genes that can serve as diagnostic and prognostic biomarkers for HCC. β-sitosterol from the DH drug and luteolin from the DS drug were found as promising small molecules for HCC. The experimental results showed that the combination of β-sitosterol and luteolin was more potent in suppressing cell proliferation, migration and inducing cell apoptosis when compared to β-sitosterol or luteolin alone. The western blot and molecular docking studies demonstrated that the potential mechanism may be related to the EGFR/AKT signaling pathway. In summary, the combination of DH and DS may resist cell proliferation, migration and promote apoptosis activity through the EGFR/AKT signaling pathway, which provides new insights for further exploring plant extract treatment for HCC.</p>