Background Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death. Traditional Chinese medicine (TCM) has special advantages in relieving HCC, while Astragalus membranaceus is commonly used in TCM treatment. However, its underlying mechanisms for treatment of HCC are unclear. Methods Differentially expressed genes (DEGs) of Astragalus membranaceus treatment in HepG2 cells were identified, and Astragalus membranaceus-gene network was constructed. The hub genes were then obtained via protein-protein interaction (PPI) analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Gene Set Enrichment Analysis (GSEA) were subsequently performed. Furthermore, prognosis genes related to HCC from The Cancer Genome Atlas Program (TCGA) was identified to explore the correlation between Astragalus membranaceus treatment and prognosis of HCC. Finally, Astragalus membranaceus-component-target network was established through SymMap. Results Twenty five DEGs (15 up-regulated and 10 down-regulated) of Astragalus membranaceus treatment in HepG2 cells were identified. Among the 25 genes, MT1F, MT1G, MT1X and HMOX1 may play essential roles. Astragalus membranaceus mainly affects the Mineral absorption pathway in HCC. A total of 256 genes (p < 0.01) related to prognosis of HCC were identified, and MT1G is a common gene between prognosis genes and DEGs. Furthermore, Astragalus membranaceus may directly down-regulate MT1G through daidzein to promote ferroptosis of HCC cells and improve prognosis for HCC. Conclusion Our study provided new understandings of the pharmacological mechanisms by which Astragalus membranaceus improves the prognosis of HCC, and showed that the combination of transcriptomics and network pharmacology is helpful to explore mechanisms of TCM and traditional medicines from other nations.