Background/Objectives: Colorectal cancer (CRC) frequently co-occurs with intestinal system diseases (ISDs), yet their molecular interplay remains poorly understood. We employed a comprehensive bioinformatics approach to elucidate shared genetic signatures and pathways between CRC and ISDs. Methods: We systematically analyzed 12 microarray and RNA-seq datasets encompassing 989 samples across seven ISDs and CRC. Differentially expressed genes (DEGs) were identified using Limma and DESeq2. Functional enrichment analysis was performed using clusterProfiler. Protein–protein interaction networks were constructed via STRING and visualized with Cytoscape to identify hub genes. Clinical significance of shared genes was further assessed through survival analysis and validated by immunohistochemistry staining of 30 paired CRC–normal tissue samples. Results: Integrating bioinformatics and machine learning approaches, we uncovered 160 shared DEGs (87 upregulated, 73 downregulated), which predominantly enriched cell metabolism, immune homeostasis, gut–brain communication, and inflammation pathways. Network analysis revealed nine key hub proteins linking CRC and ISDs, with seven upregulated (CD44, MYC, IL17A, CXCL1, FCGR3A, SPP1, and IL1A) and two downregulated (CXCL12 and CCL5). Survival analysis demonstrated the prognostic potential of these shared genes, while immunohistochemistry confirmed their differential expression in CRC tissues. Conclusions: Our findings unveil potential biomarkers and therapeutic targets, providing insights into ISD-influenced CRC progression and offering a robust foundation for improved diagnostic and treatment strategies in ISD-associated CRC.