Ischemic stroke (IS) is a leading global cause of mortality and disability, particularly prominent in patients with end-stage renal disease (ESRD). Despite clinical evidence of their comorbidity, the molecular mechanisms underlying their interaction remain elusive. This study aims to identify shared biomarkers, gene regulatory networks, and therapeutic targets through integrative bioinformatics analyses. Gene expression datasets for IS (GSE16561, GSE22255) and ESRD (GSE37171, GSE142153) were obtained from gene expression omnibus (GEO). Weighted gene co-expression network analysis (WGCNA) and differential expression genes (DEGs) analysis identified shared genes and enriched pathways. Protein-protein interaction networks were constructed using STRING with clustering algorithms. Immune cell infiltration analysis was performed via CIBERSORT. Transcriptional regulatory networks were predicted using RcisTarget and miRcode. Key gene expressions were validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in clinical samples. We identified 417 intersecting genes through WGCNA and 1712 shared differentially expressed genes. Among these, seven key genes (MRPL49, MRPS2, MRPS9, MRPS10, MRPS11, MRPS27, TFB1M) demonstrated central roles in mitochondrial function. Immune infiltration analysis revealed significant correlations with T cells and neutrophils. Pathway enrichment implicated these genes in transforming growth factor beta (TGF-β) signaling, p53 pathway, and G2/M checkpoint. Clinical validation confirmed significant downregulation of MRPS9, MRPS10, MRPS11, MRPS27 and TFB1M in comorbid patients. This study systematically elucidates the mitochondrial-immune interaction mechanisms in IS-ESRD comorbidity, highlighting the pivotal role of mitochondrial ribosomal protein (MRP) family genes in regulating cellular energetics and inflammatory responses. These findings provide new foundations for targeted therapies.