BackgroundIschemic stroke (IS) is the second leading cause of mortality worldwide, continuing to be a serious health concern. It is well known that oxidative stress and neutrophil response play vital roles in the pathophysiology of early IS. However, the complex interactions and critical genes associated with them have not been fully understood.MethodsTwo datasets (GSE37587 and GSE16561) from the Gene Expression Omnibus database were extracted and integrated as the discovery dataset. Subsequent GSVA and WGCNA approaches were used to investigate IS-specific oxidative stress-related genes (ISOSGS). Then, we explored IS-specific neutrophil-associated genes (ISNGS) using CIBERSORT analysis. Next, the protein-protein interaction network was established to ascertain candidate critical genes related with oxidative stress and neutrophil response. Furthermore, these candidate genes were validated using GSE58294 dataset and our clinical samples by RT-qPCR method. Finally, functional annotation, diagnostic capability evaluation and drug-gene interactions were performed by using GSEA analysis, ROC curves and DGIDB database.ResultIn our analysis of discovery dataset, 155 genes were determined as ISOSGS and 559 genes were defined as ISNGS. Afterward, 9 candidate genes were identified through the intersection of ISOSGS and ISNGS, PPI network construction, and filtration by degree algorithm. Then, six real critical genes, including STAT3, MMP9, AQP9, SELL, FPR1, and IRAK3, passed the validation using the GSE58294 dataset and our clinical samples. Further functional annotation analysis indicated these critical genes were associated with neutrophil response, especially neutrophil extracellular trap. Meanwhile, they had a good diagnostic performance. Lastly, 53 potential drugs targeting these genes were predicted by DGIDB database.ConclusionWe identified 6 critical genes, STAT3, FPR1, AQP9, SELL, MMP9 and IRAK3, related to oxidative stress and neutrophil response in early IS, which may provide new insights into understanding the pathophysiological mechanism of IS. We hope our analysis could help develop novel diagnostic biomarkers and therapeutic strategies for IS.