Hirschsprung disease (HSCR) and ulcerative colitis (UC) exhibit overlapping features, with studies indicating a high incidence of UC among individuals with HSCR, suggesting a potential link worth exploring at the genetic level. This study aimed to identify differentially expressed genes (DEGs) common to both conditions and evaluate their diagnostic and therapeutic potential for UC. Transcriptomic expression data from colorectal biopsies were obtained from the Gene Expression Omnibus to identify common DEGs. Functional enrichment analysis was conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes methods. Feature genes for distinguishing UC were identified using support vector machine-recursive feature elimination, LASSO regression, and random forest techniques. Receiver operating characteristic (ROC) analysis assessed the diagnostic performance of these genes, leading to a nomogram for UC prediction. Pearson correlation analysis evaluated the relationship between immune cell infiltration and feature genes, while a Protein-Protein Interaction (PPI) network examined interactions with related proteins. We identified 49 common DEGs, linked to biological processes such as "positive regulation of T cell-mediated immunity." The feature genes BEX2, GNG4, and ROGDI were consistently downregulated in UC, demonstrating diagnostic potential with AUC values exceeding 0.7. The findings suggest significant changes in immune cell abundance and highlight BEX2, GNG4, and ROGDI as promising diagnostic markers and therapeutic targets for UC.