Ulcerative colitis (UC) and rheumatoid arthritis (RA) are immune-mediated inflammatory diseases (IMIDs) with similar symptoms and common genomics. However, the relationship between UC and RA has not been investigated thoroughly. Therefore, this study aimed to establish the differentially expressed genes (DEGs) and potential therapeutic targets in UC and RA. Three microarray datasets (GSE38713, GSE1919, and GSE12251) were selected from the Gene Expression Omnibus (GEO) database for analysis. We used R software to identify the DEGs and performed enrichment analyses. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and Cytoscape software were used to construct the protein-protein interaction (PPI) network and identify the hub genes. A regulatory network based on the constructed PPI was generated using StarBase and PROMO databases. We identified a total of 1542 and 261 DEGs in UC and RA. There were 169 common DEGs identified in both UC and RA, including 63 upregulated genes (DEGs1) and nine downregulated genes (DEGs2). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of DEGs1 and DEGs2 in the PPI network revealed that the genes enriched were involved in immunity. A total of 45 hub genes were selected based on high scores of correlation; three hub genes (SRGN, PLEK, and FCGR3B) were found to be upregulated in UC and RA, and downregulated in UC patients with response to infliximab treatment. The identification of novel DEGs and hub genes in the current study contributes to a novel perception for latent functional mechanisms and presents potential prognostic indicators and therapeutic targets in UC and RA.