Diabetes is a key risk factor for ischemic stroke and negatively impacts long-term outcomes post-stroke. However, genomic studies on diabetic stroke remain insufficient. This study aims to investigate the interaction between diabetes and stroke from the acute phase to the early recovery phase by establishing a diabetic stroke animal model and comparing transcriptome sequencing results with those of non-diabetic stroke models. The study identified a greater number of downregulated genes in the diabetic stroke group compared to the non-diabetic group at different stages post-stroke. Functional enrichment analysis revealed an enhanced immune response and a relatively lower neurodegeneration potential in the diabetic group. Post-stroke, a higher presence of CD4 + T cells, eosinophils, and M1 macrophages was observed in the diabetic group. Additionally, time-series analysis identified a set of genes with time-specific expression patterns following diabetic stroke. This study underscores the role of inflammation and immune responses as potential factors exacerbating ischemic stroke in diabetes while also identifying gene regulatory networks at different stages post-stroke. These findings provide new insights into the role of diabetes in stroke and suggest potential therapeutic targets for improving outcomes in diabetic patients.