Objective To reveal the mechanism of action of AS-Ⅳ on HepG2 cells based on molecular dynamics simulation and experimental evaluation. Methods We constructed a "drug-disease" network pharmacological map, analyzed the core genes of astragaloside Ⅳ (AS-Ⅳ) in HCC, screened key signaling pathways, and established a "drug-target" molecular dynamics model. In vitro assay was used to detect migration, proliferation and invasion abilities. Flow cytometry and qRT-PCR were used to detect the effect of AS-Ⅳ on the cell cycle and apoptosis, and the expression of core gene of HepG2. Results The core target of AS-Ⅳ acting on HCC was VEGFA. Compared with the control group, the high concentration of AS-Ⅳ significantly inhibited the migration, invasion and proliferation of HepG2 cells, blocked the metastasis of HepG2 cells from G₁ to G₂ phase, promoted their apoptosis, down-regulated VEGFA expression and up-regulated TGF-β1 expression. Conclusion AS-Ⅳ may inhibit the proliferation of hepatocellular carcinoma cells through multi-target and multi-pathway.