Ischemic stroke (IS) is a complex disease with sex differences in epidemiology, presentations, and outcomes. However, the sex-specific mechanism underlying IS remains unclear. The purpose of this study was to identify key genes contributing to biological differences between sexes. First, we downloaded the gene expression data of GSE22255 from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified using R software and related packages. Second, DEGs were separately analyzed by Gene Ontology enrichment and pathways analyses. Third, protein-protein interaction (PPI) network was constructed to further investigate the interactions of DEGs. A total of 123 DEGs were identified between sexes, including 8 upregulated and 115 downregulated genes. In the PPI network, ten key genes were identified, including IL1, IL1, IL6, IL8, CXCL1, CXCL2, CXCL20, CCL4, ICAM1, and PTGS2. Functional enrichment analysis revealed that these genes were mainly enriched in biological processes of immune response and apoptotic process, also in pathways of TNF and NOD-like receptor signaling. In conclusion, the above ten genes may have a protective effect on IS females through their direct or indirect involvement in biological processes of immune response and apoptotic process, as well as in TNF and NOD-like receptor signaling pathways. The results of this study may help to gain new insights into the sex-specific mechanisms underlying IS females and may suggest potential therapeutic targets for disease treatment.