It has been indicated that there is an association between inflammatory bowel disease (IBD) and hepatocellular carcinoma (HCC). However, the molecular mechanism underlying the risk of developing HCC among patients with IBD is not well understood. The current study aimed to identify shared genes and potential pathways and regulators between IBD and HCC using a system biology approach. By performing the different gene expression analyses, we identified 871 common differentially expressed genes (DEGs) between IBD and HCC. Of these, 112 genes overlapped with immune genes were subjected to subsequent bioinformatics analyses. The results revealed four hub genes (CXCL2, MMP9, SPP1 and SRC) and several other key regulators including six transcription factors (FOXC1, FOXL1, GATA2, YY1, ZNF354C and TP53) and five microRNAs (miR-124-3p, miR-34a-5p, miR-1-3p, miR-7-5p and miR-99b-5p) for these disease networks. Protein-drug interaction analysis discovered the interaction of the hub genes with 46 SRC-related and 11 MMP9- related drugs that may have a therapeutic effect on IBD and HCC. In conclusion, this study sheds light on the potential connecting mechanisms of HCC and IBD.