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Serum extracellular vesicle (EV) microRNAs (miRNAs) are promising biomarkers for ischemic stroke (IS), but their role in transient ischemic attack (TIA) remains unclear. This study aimed to evaluate EV miRNAs as non-invasive diagnostic tools for IS and TIA. Using single-molecule sequencing, miRNAs were profiled in pooled sera from 50 IS patients and 50 controls. Altered miRNAs were validated via individual qRT‑PCR in the same cohort and tested in expanded internal (100 IS, 40 TIA, 100 controls) and external validation cohorts (32 IS, 8 TIA, 32 controls). Diagnostic performance was assessed via ROC and logistic regression analyses. Bioinformatics and in vitro oxygen-glucose deprivation/reperfusion (OGD/R) models were employed to explore mechanisms. Initial screening identified 134 differentially expressed EV miRNAs (36 upregulated, 98 downregulated) in IS. Validation confirmed significantly decreased let-7f-5p in IS and TIA, and elevated miR-486-5p and let-7b-5p in IS, with let-7b-5p higher in IS than TIA. A combined EV miRNA panel may effectively distinguish IS and TIA from controls, and stratify IS severity and TIA subsequent stroke risk. Multivariable logistic regression showed increased EV let-7b-5p independently associated with IS, and reduced let-7f-5p with IS/TIA. Bioinformatic analysis predicted FOXO1 and BDNF as key targets; decreased FOXO1 and increased BDNF were observed in IS serum and serum EVs, and FOXO1 downregulation was replicated in an OGD/R cellular model. A serum EV miRNA signature (downregulated let-7f-5p, upregulated miR-486-5p and let-7b-5p) may serve as a non-invasive biomarker panel for assessing IS severity and TIA stroke risk. Dysregulation of these miRNAs and their targets may contribute to ischemic injury pathology.