Ischemic stroke (IS) affects 11 million people annually, posing substantial clinical and economic burdens. Current therapies remain limited by time sensitivity and variable efficacy, necessitating novel biomarkers. We developed a multi-omics framework to investigate senescence-associated gene regulation in IS. After normalizing GSE22255 and GSE58294 datasets, we systematically identified aging-related differentially expressed genes (DEGs). Functional annotation via Gene Set Enrichment Analysis (GSEA) and machine learning-driven Weighted Gene Co-expression Network Analysis (WGCNA) identified core genetic signatures validated in the GSE16561 cohort. Key regulators underwent single-gene profiling, immune microenvironment evaluation, and transcriptional network analysis. Reverse transcription-quantitative PCR (RT-qPCR) confirmed bioinformatics findings. We identified 132 senescence-related DEGs, with PTGS2 emerging as a key biomarker. Pathway analyses revealed significant NF-κB, HIF-1, and TGF-β signaling pathway activation. CIBERSORT-based immune profiling showed altered lymphocyte/macrophage ratios in IS patients. Drug-gene interaction analysis identified nine therapeutic compounds, including etodolac targeting NFE2L2 and PTGS2. A strong positive correlation (r = 0.72, p < 0.001) between NFE2L2 and PTGS2 expression was observed. This study establishes senescence-related genes as promising biomarkers and therapeutic targets for IS, particularly through NFE2L2-PTGS2 interactions, providing a foundation for developing immunomodulatory and targeted therapies.© 2025. The Author(s).