Background: Hepatocellular carcinoma (HCC/LIHC) is the most common type of primary liver cancer, which is a leading cause of cancer death worldwide. Patients with HCC have a short survival time after diagnosis. Unfortunately, there are no effective treatments for advanced or aggressive HCC. Thus, the rapid development of new therapeutic drugs or treatment methods for HCC is urgently needed. Methods: Bioinformatic tools and computer-aided predictions advance the processes of drug development. In this study, we incorporated bioinformatic analyses and computer-aided drug development processes to investigate the potential application of bilobetin, a bioactive compound of bioflavonoid, as a therapeutic agent for HCC treatment. Results: Our results revealed that 4 out of 20 predicted hub target genes of bilobetin displayed functional importance in cancer-related signaling pathways in different cancers, including HCC. Importantly, the mRNA expression levels of these four key hub genes (VEGFA, SRC, MMP9, and CDK1) were significantly different between normal and HCC tumor samples. Their expression levels were significantly associated with the clinical survival outcomes of HCC patients, as well as the immune cell infiltration levels in the HCC tumor microenvironment. In addition, these four genes showed significant co-expression correlated with immune checkpoint genes, including CD274, PDCD1, CTLA4, and CD47. Furthermore, we used computer-aided approaches to investigate the binding affinity and potential binding mechanisms between bilobetin and target proteins encoded by four key hub genes. Conclusions: In conclusion, our study shed light on the potential application of the bioactive bioflavonoid molecule bilobetin in LIHC treatment by regulating four key hub genes.