BACKGROUND: Multiple Sclerosis (MS) and Inflammatory Bowel Disease (IBD) are immune-mediated disorders with a significant concurrence among patients and share considerable genetic variations and environmental factors. This study aimed to identify shared differentially expressed genes (DEGs) between MS and IBD using mRNA expression data analysis to improve understanding of their co-occurrence and relationship between these two diseases and potentially achieve better disease management. METHODS: Blood mRNA expression data from case-control studies on MS and IBD were retrieved from the NCBI-GEO database and analyzed using GEO2R to identify differentially expressed genes (DEGs) (p ≤ 0.05, fold change ≥ 1.5). Shared DEGs were studied for expression patterns, and protein-protein interaction (PPI) networks, biological processes, pathways, and hub genes were identified. DEGs and their single nucleotide variations (SNVs) from genome-wide association studies (GWAS) were further analyzed using in silico tools to explore functional implications. RESULTS: Five studies each for MS and IBD were included, following inclusion/exclusion criteria. Thirty-one shared DEGs were identified, with 25 showing inverse regulation patterns: up-regulated in MS and down-regulated in IBD. The intergenic SNV rs2688608 near PLAU was found to be functionally relevant to both the diseases. Pathway analysis revealed shared processes, including leukocyte extravasation, I-kappa B phosphorylation, viral protein interactions with cytokines, and NF-kappa B signalling. TNF, PLAU, VCAM1, and CX3CR1 were identified as hub genes, suggesting them as potential therapeutic targets. These findings highlight shared mechanisms in MS and IBD pathogenesis. CONCLUSION: This study identified shared molecular signatures between MS and IBD, supporting the concept of interconnected disease processes. The identified genes and pathways associated with inflammation and immune response offer valuable insights for further research into potential therapeutic targets for MS and IBD and their co-occurrence.