To investigate the potential therapy targets and pharmacological mechanism of traditional Chinese medicine (TCM) Xihuang pill in liver cancer based on network pharmacology. Drug ingredients-target network was constructed based on the target sets of Xihuang pill and liver cancer. The overlapping genes between Xihuang pill targets and liver cancer-related molecular targets were investigated using comparative analysis. Moreover, the PPI network and module was constructed based on overlapping genes and hub nodes, respectively, followed by the pathway enrichment analysis. A drug ingredients-target network was established with 1184 nodes and 11035 interactions. Moreover, a total of 106 overlapping genes were revealed between drug targets and liver cancer molecular targets. Furthermore, a PPI network and 4 modules were further investigated based on overlapping genes, respectively. These hub nodes such as VEGFA and EGFR were mainly enriched in GO functions including positive regulation of MAP kinase activity, activation of protein kinase activity, regulation of MAP kinase activity, and pathways like proteoglycans in cancer, bladder cancer, and estrogen signaling. VEGFA and EGFR might be potential therapy targets of Xihuang pill in liver cancer. Furthermore, the effect of Xihuang pill on liver cancer might be realized by targeting VEGFA and EGFR in pathways like proteoglycans in cancer and estrogen signaling. Copyright © 2020 Xu Zhao et al.