Background <p>Diabetes is considered to be a risk factor for colon cancer (CC), and CC patients with diabetes tend to have a worse prognosis. However, the underlying mechanism of this condition remains unclear. This study aims to elucidate the relationship between diabetes and CC further, and to find effective therapeutic targets.</p> Methods <p>Transcription and clinical information data were acquired from the Gene Expression Omnibus (GEO) database, accessed differentially expressed genes (DEGs) between different groups, and enriched function and pathway by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. We conducted a weighted gene co-expression network analysis (WGCNA) to obtain significant modules and hub genes of diabetic-related CC. A receiver operating characteristic curve (ROC) analysis and Kaplan-Meier plotter were performed to diagnosis and prognosis prediction. Using the Connectivity Map (CMap) database to predict small molecule compounds, and employed molecular docking to simulate the binding conformation of the potential agent and key targets. Moreover, CIBERSORT was used to depict the immune infiltration in diabetic-related CC. The correlations between tumor mutation burden score, microsatellite instability score, and hub DEGs expression were performed by Spearman’s correlation.</p> Results <p>In this study, 633 DEGs were identified from the tumor (<i>n</i> = 42) and the normal colon mucosa samples (<i>n</i> = 42), and 133 DEGs were identified from type 2 diabetes mellitus (T2DM) (<i>n</i> = 46) and non-T2DM samples (<i>n</i> = 38). We obtained a gene module including 1183 genes significantly related to CC patients with diabetes, and finally, the intersection of tumor-associated DEGs, diabetes-associated DEGs, and WGCNA identified 11 hub DEGs. The hub DEGs had great diagnostic and prognostic values for CC and diabetes. We found the small-molecule compound NVP-BEZ235 according to its high binding affinity to the targets and exhibited the molecular docking landscape including CDC42BPA, COX6A1, PON2, TM9SF2, UBBE2K, UBR2, ZC3H14, and ZNF106. In addition, we found the immune-infiltrating differences between CC patients with diabetes and those without diabetes. The expression of hub DEGs was significantly correlated with tumor mutation burden and microsatellite instability.</p> Conclusion <p>Diabetes plays an important role in CC pathogenesis, and NVP-BEZ235 may be a promising therapeutic drug for CC patients with diabetes.</p>