Background: Despite the increasing number of research endeavors dedicated to investigating the relationship between colorectal carcinoma (CRC) and hepatocellular carcinoma (HCC), the underlying pathogenic mechanism remains largely elusive. The aim of this study is to shed light on the molecular mechanism involved in the development of this comorbidity. Methods: The gene expression profiles of CRC (GSE90627) and HCC (GSE45267) were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the common differentially expressed genes (DEGs) of psoriasis and atherosclerosis, three kinds of analyses were performed, namely, functional annotation, protein-protein interaction (PPI) network and module construction, and hub gene identification, survival analysis and co-expression analysis. Results: A total of 150 common downregulated differentially expressed genes and 148 upregulated differentially expressed genes were selected for subsequent analyses. The significance of chemokines and cytokines in the pathogenesis of these two ailments is underscored by functional analysis. Seven gene modules that were closely connected were identified. Moreover, the lipopolysaccharide-mediated signaling pathway is intricately linked to the development of both diseases. Finally, 10 important hub genes were identified using cytoHubba, including CDK1, KIF11, CDC20, CCNA2, TOP2A, CCNB1, NUSAP1, BUB1B, ASPM, and MAD2L1. Conclusion: Our study reveals the common pathogenesis of colorectal carcinoma and hepatocellular carcinoma. These common pathways and hub genes may provide new ideas for further mechanism research.Copyright © 2023 Gao, Li, Wu, Xiao, Huang, Deng, Yang, Tian, Cao, Zhang, Gu and Yu.