Background. Neuronal apoptosis, which is the primary pathological transform of cerebral injury following ischemic stroke (IS), is considered to be induced by endoplasmic reticulum stress (ERS) by numerous reports. However, ERS biomarkers in IS have not been fully identified yet. Consequently, the present study is aimed at exploring potential blood biomarkers by investigating the molecular mechanisms of ERS promoting neuronal apoptosis following IS development. Methods. A comprehensive analysis was performed with two free-accessible whole-blood datasets (GSE16561 and GSE37587) from the Gene Expression Omnibus database. Genetic information from 107 IS and 24 healthy controls was employed to analyze the differentially expressed genes (DEGs). Genes related to ERS (ERS-DEGs) were identified from the analysis. Enrichment analyses were performed to explore the biofunction and correlated signal pathways of ERS-DEGs. Protein-protein interaction (PPI) network and immune correlation analyses were performed to identify the hub genes along with their correspondent expressions and functions, all of which contributed to incremental diagnostic values. Results. A total of 60 IS-related DEGs were identified, of which 27 genes were confirmed as ERS-DEGs. GO and KEGG enrichment analysis corroborated that upregulated ERS-DEGs were principally enriched in pathways related to immunity, including neutrophil activation and Th17 cell differentiation. Moreover, the GSEA and GSVA indicated that T cell-related signal pathways were the most considerably immune pathways for ERS-DEG enrichment. A total of 10 hub genes were filtered out via the PPI network analysis. Immune correlation analysis confirmed that the expression of hub genes is associated with immune cell infiltration. Conclusions. By integrating and analyzing the two gene expression data profiles, it can be inferred that ERS may be involved in the development of neuronal apoptosis following IS via immune homeostasis. The identified hub genes, which are associated with immune cell infiltration, may serve as potential biomarkers for relative diagnosis and therapy.